Systems and methods for treating inflammatory bowel disease using feedback controlled sacral neuromodulation

Abstract

Systems and methods for treating Inflammatory Bowel Disease (IBD) using neuromodulation are described herein. For example, IBD can be treated by delivering an electrical signal to one or more sacral nerves of a patient via an implanted signal delivery device positioned proximate one or more of the patient's sacral nerves. In some embodiments, the stimulation is delivered in discrete stimulation sessions. The timing of the stimulation sessions can be based on one or more feedback control loops.

Description

SYSTEMS AND METHODS FOR TREATING INFLAMMATORY BOWEL DISEASE USING FEEDBACK CONTROLLED SACRAL NEUROMODULATIONCROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 608,723, filed December 1 1 , 2023, the disclosure of which is incorporated by reference herein in its entirety.TECHNICAL FIELD

[0002] The present technology is directed toward electrically modulating nervous tissue to treat a patient condition.BACKGROUND

[0003] Inflammatory Bowel Disease (IBD) is a digestive disorder characterized by chronic inflammation of the gastrointestinal tract. IBD includes both Crohn's disease, which causes intermittent inflammation of the gastrointestinal tract, and ulcerative colitis, which causes continuous inflammation of the colon. Both Crohn's disease and ulcerative colitis cause similar patient symptoms, including patient discomfort (e.g., abdominal pain), abnormal gastrointestinal tract function (e.g., diarrhea), and other complications (e.g., fever, weight loss, etc.). IBD is typically treated using pharmaceutical therapies including anti-inflammatory drugs and immune system suppressors. In extreme cases, patients may even undergo surgery to remove inflamed or damaged portions of the colon or other portions of the digestive tract. However, neither pharmaceuticals nor surgery cure IBD, and symptoms often persist or recur during or after treatment. Moreover, in certain patients, pharmaceuticals and surgery have minimal efficacy and / or induce unwanted side effects. Accordingly, a need exists for improved treatments for IBD.

[0004] Neurological stimulation systems generally have a signal generator that generates electrical pulses, and one or more signal delivery devices such as leads that deliver the electrical pulses to neurological tissue or muscle tissue. The delivered electrical pulses modulate neural activity to treat an underlying patient condition. Forexample, neurostimulation has been used to treat various disorders such as pain, movement disorders, cardiac disorders, and various other medical conditions. Sacral neuromodulation (SNM) is a type of neuromodulation in which electrical stimulation is applied to one or more sacral nerves to treat a patient condition. SNM has been used to treat various urological disorders, including urinary retention, urinatory incontinence, and fecal incontinence.BRIEF DESCRIPTION OF THE DRAWINGS

[0005] Figure 1 is a partially schematic illustration of an implantable sacral neuromodulation system positioned at a patient's sacral region to deliver electrical signals in accordance with some embodiments of the present technology.

[0006] Figure 1 B illustrates sacral nerve anatomy of a patient, along with a portion of a signal delivery device of the system of Figure 1 A shown as implanted at a representative location in accordance with some embodiments of the present technology.

[0007] Figure 2A is a partially schematic illustration of an electrical signal generated in accordance with some embodiments of the present technology.

[0008] Figure 2B is a partially schematic illustration of another electrical signal generated in accordance with some embodiments of the present technology.

[0009] Figure 3 is a flowchart of a method of using sacral nerve stimulation to treat Inflammatory Bowel Disease in accordance with embodiments of the present technology.

[0010] Figure 4 is a flowchart of another method of using sacral nerve stimulation to treat Inflammatory Bowel Disease in accordance with embodiments of the present technology.DETAILED DESCRIPTIONA. Introduction

[0011] The present technology is directed to treating Inflammatory Bowel Disease (IBD) using neuromodulation. For example, many of the embodiments described herein include electrically stimulating one or more sacral nerves of a patient to treat thepatient's IBD. As described in detail throughout this Detailed Description, the stimulation can be administered to the patient during discrete stimulation sessions or periods that can have a duration of between, for example, 15 minutes and 4 hours. In some embodiments, the stimulation sessions are timed to coincide with certain patient activities or states. For example, the stimulation sessions can be timed to occur during periods in which the patient's body is in a naturally anti-inflammatory or naturally pro- inflammatory state, and / or while the patient is asleep or prandial. In other embodiments, the stimulation sessions are restricted to occur when the patient is located in a particular geographic area. To facilitate this, the systems and methods describe herein incorporate feedback control loops based on one or more sensed parameters.

[0012] Unless otherwise stated, the terms "generally," "about," and "approximately" refer to values within 10% of a stated value. For example, the use of the term "about 100" refers to a range of 90 to 110, inclusive. In instances in which relative terminology is used in reference to something that does not include a numerical value, the terms are given their ordinary meaning to one skilled in the art.

[0013] As used herein, and unless otherwise noted, the terms "modulate," "modulation," "stimulate," and "stimulation" refer generally to electrical signals that have an inhibitory, excitatory, and / or other effect on a target neural population. Accordingly, a sacral nerve "stimulator" can have an inhibitory effect and / or an excitatory effect on certain neural populations.

[0014] As used herein, the terms "electrical therapy signal," "electrical signal," "therapy signal," "signal," and other associated terms are used interchangeably and generally refer to an electrical signal that can be characterized by one or more parameters, such as frequency, pulse width, and / or amplitude.

[0015] As used herein, "proximate a target neural population" refers to the placement of a signal delivery element such that it can deliver electrical stimulation to the target neural population. For example, if the target population includes the third sacral spinal nerve, "proximate the target neural population" includes, but is not limited to, the relative lead positions described and shown in Figure 1 B, as well as other positions not expressly described herein.

[0016] Specific details of certain embodiments of the disclosure are described below with reference to methods for modulating one or more target neural populations(e.g., nerves) or sites of a patient, and associated implantable structures for providing the modulation. Although selected embodiments are described below with reference to modulating the sacral nerves, the modulation may in some instances be directed to other neurological structures and / or target neural populations and / or other neurological tissues throughout the body. For example, some embodiments may include modulating the vagus nerve, the splenic nerve, the splanchnic nerve, and / or other peripheral nerves. Some embodiments can have configurations, components, and / or procedures different than those described herein, and other embodiments may eliminate particular components and / or procedures. A person of ordinary skill in the relevant art, therefore, will understand that the present disclosure may include other embodiments with additional elements, and / or may include other embodiments without several of the features shown and described below with reference to Figures 1 A-4.B. Representative Embodiments of Sacral Neuromodulation Systems and Associated Stimulation Waveforms

[0017] Figure 1A schematically illustrates a sacral neuromodulation system 100 ("the system 100") implanted to stimulate a patient's sacral nerves and configured in accordance with embodiments of the present technology. The system 100 includes a signal generator 1 10 and a signal delivery device 120. The signal generator 110 can be implanted and / or implantable subcutaneously within the patient P. For example, in the illustrated embodiment the signal generator 110 is implanted subcutaneously at the lower back / upper buttock area of the patient P (e.g., adjacent but posterior to the iliac crest IC and / or iliac fossa IF).

[0018] The signal delivery device 120 extends from the signal generator 1 10 and can be implanted within the patient P proximate a target neural population. In some embodiments, the target neural population includes one or more of the sacral spinal nerves (e.g., the S1 sacral nerve, the S2 sacral nerve, the S3 sacral nerve and / or the S4 sacral nerve). Accordingly, in some embodiments the signal delivery device 120 can extend through one of the sacral foramen S1 -S4 (the illustrated embodiment depicts the signal delivery device 120 extending through the sacral foramen S1 ) and adjacent one or more sacral spinal nerves when implanted. More specifically, the signal delivery device 120 can be implanted proximate the S1 sacral nerve, the S2 sacral nerve, the S3 sacral nerve, and / or the S4 sacral nerve. The signal delivery device 120 can carryfeatures configured to administer therapy to the target neural population. For example, the signal delivery device 120 can include one or more lead(s) or lead bodies 122 extending from the signal generator 110 toward the target neural population (e.g., toward the S3 sacral nerve). As described in greater detail with reference to Figure 1 B, the lead 122 can include or carry one or more electrical contacts or electrodes (e.g., ring electrodes, cuff electrodes, and / or other suitable electrical contacts) that deliver electrical signals to the target neural population.

[0019] In operation, the signal generator 1 10 can generate and transmit signals (e.g., electrical signals) to the signal delivery device 120. In turn, the signal delivery device 120 can deliver the electrical signals to the target neural population, e.g., to electrically modulate neurons within the target neural population to induce a therapeutic effect in the patient. Representative electrical signals that can be generated by the signal generator 1 10 and delivered to the patient P via the signal delivery device 120 are described in greater detail below with reference to Figures 2A and 2B.

[0020] The signal generator 110 can include a machine-readable (e.g., computer- readable) medium containing instructions for generating and transmitting electrical signals. Accordingly, generating electrical signals in accordance with the methods described herein can include executing computer-executable instructions contained by, on, or in computer-readable media located within the signal generator 1 10. The signal generator 110 can also include one or more processors for executing the machine- readable instructions, memory unit(s), batteries (rechargeable and / or non- rechargeable), communication devices (e.g., an antenna), and / or other software or hardware-based components. As shown in Figure 1 A, the signal generator 1 10 can include a single housing for storing some or all of the foregoing components, although in other embodiments some or all of the foregoing components can be stored in separate housings.

[0021] In some embodiments, the signal generator 1 10 can be configured to communicate with one or more external controllers. For example, the signal generator 110 can wirelessly communicate with a physician controller (not shown) that is external to the patient P. A physician or other healthcare provider can use the physician controller to program the signal generator 1 10, e.g., to select parameters for the electrical signal to be generated by the signal generator 110. In some embodiments,the signal generator 1 10 can also communicate with a patient controller that is external to the patient P. The patient P can use the patient controller to control various aspects of the therapy provided by the signal generator 1 10. For example, the patient may be able to start and stop electrical stimulation therapy using the patient controller, and / or control certain parameters (e.g., amplitude) of the electrical stimulation using the patient controller. In some embodiments, the signal generator 1 10 can transmit data to the physician controller and / or the patient controller for user review. For example, the signal generator 110 may periodically (or on demand) transmit data associated with one or more of electrode impedance, battery power, program settings (e.g., current signal parameters), historical program settings (e.g., historical signal parameters), program / parameter changes, usage data (e.g., stimulation start and stop times), or the like. The physician controller and the patient controller can include a dedicated controller device, or be implemented as an application on a smartphone, tablet, etc.

[0022] In some embodiments, the system 100 can include a sensor 1 15. As illustrated, the sensor 1 15 can be coupled to or contained within the signal generator 110. In other embodiments, the sensor 115 can be implanted separately from the signal generator 1 10. In yet other embodiments, the sensor 115 can be external to the patient and included as a wearable device. The sensor 115 can measure one or more physiological parameters associated with the patient. For example, the sensor 1 15 can measure heart rate, heart rate variability, body temperature, respiratory rate, blood oxygen level, various biomarker concentrations (e.g., cytokines, chemokines, or other molecules), or the like. Additionally or alternatively, the sensor 1 15 can be an accelerometer, gyroscope, or other motion sensor that measures a patient's activity or movement. Further yet, the sensor 115 can be a GPS or other location tracker for tracking a location of the patient. Although shown as a single sensor 115, the system 100 can include any number of sensors 1 15, such as one, two, three, four, or more sensors. As described below in Section C of this Detailed Description, the sensor can be incorporated into one or more feedback loops for controlling a timing of delivering sacral nerve stimulation using the system 100.

[0023] In some embodiments, the system 100 can be implanted in the patient P to treat IBD or an associated condition, including Crohn's disease or ulcerative colitis. For example, the system 100 can deliver electrical signals to one or more sacral nerves of the patient to electrically stimulate the one or more sacral nerves. As described in detailthroughout this Detailed Description, the electrical signal can treat, reduce, and / or ameliorate the IBD. For example, the electrical signal may reduce one or more IBD- related symptoms (e.g., diarrhea, abdominal pain, weight loss, etc.), and / or reduce inflammation causing the one or more symptoms. Moreover, although shown as providing unilateral stimulation, in some embodiments the system 100 can be configured to provide bilateral sacral nerve stimulation to treat the patient's IBD. Additional details of electrical signals and stimulation regimes for treating IBD are described below with reference to Figures 2A and 2B.

[0024] In some embodiments, prior to receiving the signal generator 110, the patient P undergoes a trial period during which the patient P receives electrical stimulation to determine whether the patient P responds favorably to stimulation therapy. During the trial period, the patient P may use a temporary, external trial stimulator that generates and transmits electrical signals to the target neural population via the signal delivery device 120 or another implanted signal delivery element. If the patient responds favorably during the trial period, the patient may elect to have the signal generator 1 10 implanted to facilitate chronic stimulation therapy. In some embodiments, the trial period can be omitted, and the signal generator 1 10 can be implanted without the patient previously receiving stimulation from a temporary external signal generator.

[0025] Figure 1 B is an illustration of a sacral plexus SP of a patient, along with a distal portion of the lead 122 shown as implanted at a representative location. The sacral plexus SP includes four sacral spinal nerves: the first sacral nerve S1 , the second sacral nerve S2, the third sacral nerve S3, and the fourth sacral nerve S4. The lead 122 is shown as extending along (e.g., proximate to) the third sacral nerve S3 such that it can electrically stimulate the third sacral nerve S3. In other embodiments, however, the lead 122 can be positioned proximate other sacral spinal nerves, and / or proximate other nerve fibers of the sacral plexus SP, to electrically stimulate other target tissue. In yet other embodiments, the lead 122 can be positioned proximate other neural structures of the sacral plexus SP.

[0026] Figure 1 B also shows a plurality of electrodes or electrical contacts 124a-d carried by the lead 122, as described previously. Electrical signals generated by the signal generator 1 10 and transmitted through the lead 122 can be delivered to the targetneural population via the electrodes 124a-d. Although shown as having four electrodes, the lead 122 can have more or fewer electrodes, such as one, two, three, four, five, six, seven, eight, or more.

[0027] In some embodiments, test stimulation may be administered to a patient during a procedure to implant the signal delivery device 120. This can be done to ensure adequate placement of the lead 122, e.g., to ensure that the electrical signals delivered via the lead 122 are applied to the target neural population. In some embodiments, test stimulation is administered at or above a sensory threshold during an implant procedure such that the patient can give intraoperative feedback about the location of the sensation, and thus the location of the lead 122. In some embodiments, test stimulation is administered at or above a motor threshold during the implant procedure, and a motor response to the test stimulation is observed to determine the location of the lead 122. In other embodiments, however, placement of the lead 122 can be confirmed using other techniques (e.g., imaging), such that intraoperative test stimulation is not required.

[0028] Figure 2A is a partially schematic illustration of a representative electrical signal waveform 200 ("the signal 200") generated in accordance with embodiments of the present technology. The signal 200 can be generated by the system 100 (e.g., by the signal generator 110) described above with respect to Figures 1A and 1 B, or by another sacral neuromodulation system. As described throughout this Detailed Description, the signal 200 can be delivered to a patient's sacral region to treat a patient condition such as IBD.

[0029] The signal 200 includes repeating pulse periods 201 , with each pulse period 201 having a biphasic pulse 202 followed by an interpulse interval 212. Each pulse 202 includes a first pulse phase 203 having a first polarity followed by a second pulse phase 204 having a second polarity that is opposite the first polarity. For example, in the illustrated embodiment the first pulse phase 203 is an anodic pulse phase and the second pulse phase 204 is a cathodic pulse phase, although in other embodiments the anodic pulse phase and the cathodic pulse phase can be reversed, such that the cathodic pulse phase is the first pulse phase and the anodic pulse phase is the second pulse phase. In other embodiments, the signal 200 includes monophasic pulses. In such embodiments, the signal 200 includes repeating pulses of the same polarity.

[0030] In some embodiments, the first pulse phase 203 is separated from the second pulse phase 204 by an interphase interval 208. During the interphase interval 208, the amplitude of the signal 200 can return to baseline (e.g., zero or about zero), although in other embodiments the amplitude of the signal 200 during the interphase interval 214 can be a non-zero value. In some embodiments, the interphase interval 208 is omitted, and the signal 200 transitions directly from the first pulse phase 203 to the second pulse phase 204.

[0031] The first pulse phase 203 can have a pulse width 206 within a pulse width range of from about 100 microseconds to about 2 milliseconds. For example, the first pulse phase 203 can have a pulse width 206 within a pulse width range of from about 100 microseconds to about 1 .5 milliseconds, or from about 100 microseconds to about 1 millisecond, or from about 100 microseconds to about 800 microseconds, or from about 200 microseconds to about 700 microseconds, or from about 200 microseconds to about 600 microseconds, or from about 300 microseconds to about 700 microseconds, or from about 300 microseconds to about 600 microseconds, or from about 300 microseconds to about 500 microseconds, or from about 400 microseconds to about 600 microseconds, or from about 400 microseconds to about 500 microseconds. For example, in some embodiments the pulse width 206 can be about 100 microseconds, about 150 microseconds, about 200 microseconds, about 250 microseconds, about 300 microseconds, about 350 microseconds, about 400 microseconds, about 450 microseconds, about 500 microseconds, about 550 microseconds, about 600 microseconds, about 650 microseconds, or about 700 microseconds. The foregoing pulse width ranges and values are provided by way of example only — in some embodiments, the electrical signals described herein may have pulse width values outside the foregoing ranges.

[0032] In some embodiments, the second pulse phase 204 has the same or about the same pulse width as the first pulse phase 203. Accordingly, the second pulse phase 204 can have any of the pulse widths recited above with respect to the first pulse phase 203. In other embodiments, however, the second pulse phase 204 can have a different pulse width than the first pulse phase 203. For example, if the first pulse phase 203 has a pulse width of 400 microseconds or less, the second pulse phase 204 may have a pulse width of 600 microseconds or more. Likewise, if the first pulse phase 203 has a pulse width of 600 microseconds or more, the second pulse phase 204 may have apulse width of 400 microseconds or less. In general, when the second pulse phase 204 has a different pulse width than the first pulse phase 203, the pulse width of the second pulse phase 204 can be 50%, 60%, 70%, 80%, 90%, 1 10%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190% or 200% of the pulse width of the first pulse phase 203.

[0033] Regardless of whether the first pulse phase 203 and the second pulse phase 204 have the same pulse width, a total charge delivered during the second pulse phase 204 can be equal or approximately equal in magnitude and opposite in polarity from the total charge delivered during the first pulse phase 203. In this way, the second pulse phase 204 is a charge balancing pulse that prevents or at least reduces charge buildup at the electrode used to deliver the signal 200. Accordingly, in embodiments for which the first pulse phase 203 and the second pulse phase 204 have an equal or approximately equal pulse width, the first pulse phase 203 and the second pulse phase 204 can have an equal or approximately equal and opposite amplitude. In embodiments in which the first pulse phase 203 and the second pulse phase 204 have different pulse widths, the first pulse phase 203 and the second pulse phase 204 can have different amplitudes such that the total charge delivered during the first pulse phase 203 and the second pulse phase 204 remains approximately the same. In other embodiments, the pulse 202 can be charge imbalanced, such that the first pulse phase 203 and the second pulse phase 204 do not deliver charges of the same magnitude. In such embodiments, charge buildup at the electrode may passively dissipate.

[0034] The interpulse interval 212 is a quiescent period between sequential pulses 202. During the interpulse interval 212, the signal 200 can return to a baseline amplitude (e.g., zero or about zero) such that little to no charge is administered to the patient. In some embodiments, the interpulse interval can be within an interpulse interval range of from about 1 millisecond to about 1 second, such as from about 5 milliseconds to about 500 milliseconds, or from about 50 milliseconds to about 500 milliseconds, or from about 100 milliseconds to about 300 milliseconds. The foregoing interpulse interval ranges and values are provided by way of example only — in some embodiments, the electrical signals described herein may have interpulse interval values outside the foregoing ranges. In some embodiments, the duration of the interpulse interval 212 can be set independently from the duration of the pulses 202. In other embodiments, the duration of the interpulse interval 212 is set based on a selected pulse 202 duration and desired signal frequency.

[0035] The duration of the pulse period 201 determines the frequency of the signal 200. For example, if the duration of the pulse period 201 is 200 milliseconds, then the frequency of the signal is 5 Hz (i.e., five pulse periods 201 are delivered per second). The signal 200 can have a frequency between about 0.5 Hz and about 50 Hz. For example, the signal 200 can have a frequency within a frequency range of from about 1 Hz to about 40 Hz, or from about 1 Hz to about 30 Hz, or from about 1 Hz to about 25 Hz, or from about 1 Hz to about 20 Hz, or from about 1 Hz to about 15 Hz, or from about 5 Hz to about 15 Hz, or from about 1 Hz to about 12 Hz, or from about 1 Hz to about 10 Hz, or from about 2 Hz to about 8 Hz, or from about 3 Hz to about 7 Hz, or from about 4 Hz to about 6 Hz, or from about 4.5 Hz to about 5.5 Hz, or from about 4.8 Hz to about 5.2 Hz. In other embodiments, the signal 200 can have a frequency of about 0.5 Hz, about 1 Hz, about 2 Hz, about 3 Hz, about 4 Hz, about 5 Hz, about 6 Hz, about 7 Hz, or about 8 Hz. In some embodiments, the signal 200 can have a frequency of about 4.2 Hz, about 4.4 Hz, about 4.6 Hz, about 4.8 Hz, about 5.0 Hz, about 5.2 Hz, about 5.4 Hz, about 5.6 Hz, or about 5.8 Hz. The foregoing frequency ranges and values are provided by way of example only — in some embodiments, the electrical signals described herein may have frequency values outside the foregoing ranges.

[0036] The pulses 202 can have a current amplitude between about 0.1 mA and about 20 mA. For example, in some embodiments the pulses 202 have a current amplitude within a current amplitude range of from about 0.5 mA to about 15 mA, or from about 1 mA to about 12 mA, or from about 2 mA to about 12 mA, or from about 3 mA to about 10 mA. The pulses 202 can also have a voltage amplitude between about 0.1 V and 15 V. For example, in some embodiments the pulses 202 have a voltage amplitude within a voltage amplitude range of from about 0.1 V to about 10 V, or from about 0.2 V to about 8 V, or from about 0.5 V to about 4 V. In some embodiments, the amplitude (e.g., the current amplitude and / or the voltage amplitude) of the signal 200 is set based on an individual patient's sensory threshold and / or motor threshold. For example, in some embodiments the pulses 202 have a peak amplitude that is below the sensory or perception threshold of the patient. In such embodiments, the patient generally cannot actively feel the signal 200 as it is being administered. For example, the pulses 202 may have an amplitude that is 50% of sensory threshold, 60% of sensory threshold, 70% of sensory threshold, 80% of sensory threshold, 90% of sensory threshold, or 95% of sensory threshold. In other embodiments, the pulses 202 have anamplitude that is at or above the sensory threshold, such that the patient can perceive the signal 200 being delivered. In yet other embodiments, the pulses 202 have an amplitude that is below the motor threshold of the patient. In such embodiments, the signal 200 does not induce clinically discernable movement (e.g., muscle twitching) in the patient while being administered. For example, the pulses 202 may have an amplitude that is 50% of motor threshold, 60% of motor threshold, 70% of motor threshold, 80% of motor threshold, 90% of motor threshold, or 95% of motor threshold.

[0037] In some embodiments, electrical signals generated in accordance with the present technology can have one more ramped parameters. For example, Figure 2B illustrates an electrical signal 250 ("the signal 250") with a ramped amplitude in accordance with some embodiments of the present technology. The signal 250 can be generally similar to the signal 200, and can have any of the parameters and parameter values described above in connection with the signal 200. However, relative to the signal 200, an amplitude of the of the signal 250 can be ramped such that a peak amplitude of the signal 250 changes over time. In the illustrated embodiment, for example, the signal 250 includes a plurality of pulses 252 (five pulses 252a-252e are shown), with each sequential pulse 252 having a different amplitude than the preceding pulse 252. More specifically, the amplitude of the signal 250 increases from pulse 252a to pulse 252c, and then decreases from pulse 252c to pulse 252e. This pattern can then be repeated. In some embodiments, the signal 250 includes multiple pulses 252 at a common amplitude before being ramped up or down to a different amplitude (e.g., multiple pulses are delivered with an amplitude equal to the pulse 252a before the signal 250 is ramped to delivering pulses with an amplitude equal to the pulse 252b). Although shown as being ramped in two directions, in other embodiments the signal 250 is ramped only in a single direction (e.g., the amplitude is either increased or decreased, but not both), until a maximum or minimum amplitude is reached.

[0038] In some embodiments, other parameters of the signal 250 (e.g., pulse width, interpulse interval, frequency, etc.) can remain constant (e.g., unchanged) as the amplitude of the pulses 252 is ramped. In other embodiments, one or more other parameters can be ramped, in addition to the amplitude being ramped. For example, in some embodiments both a pulse width and an amplitude of the pulses 252 is ramped. In such embodiments, the pulse width of the pulses 252 may be inversely ramped with the amplitude, such that as the amplitude increases, the pulse width decreases, andvice versa. Moreover, in some embodiments the pulse width, frequency, or other parameter is ramped instead of the amplitude.

[0039] In some embodiments, the electrical signals described herein (e.g., the signal 200 of Figure 2A and the signal 250 of Figure 2B) are administered during discrete stimulation sessions or periods that have a duration less than 24 hours. For example, the stimulation sessions may have a duration of between about 15 minutes and about 4 hours, or between about 15 minutes and about 3 hours, or between about 15 minutes and about 2 hours, or between about 30 minutes and about 3 hours, or between about 30 minutes and about 2 hours, or between about 30 minutes and about 1.5 hours, or between about 45 minutes and about 1 .5 hours. In some embodiments, the stimulation sessions can have a duration of about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours. The patient can receive one or more stimulation sessions per day. For example, in some embodiments the patient receives a single stimulation session per day. In other embodiments, the patient receives multiple (e.g., two, three, four, etc.) discrete stimulation sessions per day. During periods between stimulation sessions, the patient generally does not receive any stimulation, or at least any clinically meaningful stimulation. The foregoing representative stimulation period durations are provided by way of example only — in some embodiments, the electrical signals described herein may be applied during stimulation sessions having different durations. One expected advantage of delivering stimulation during discrete stimulation sessions having a relatively short duration is that doing so may reduce the frequency with which the patient must recharge the power source in the signal generator. Another expected advantage is that it may reduce the likelihood the patient becomes desensitized (e.g., habituates) to the stimulation. In some embodiments, however, electrical stimulation is applied for 24 hours per day.

[0040] The electrical signals can be administered intermittently or continuously during the stimulation sessions. For example, the electrical signals can be administered continuously (e.g., without interruption) during the entirety of the stimulation session. Alternatively, the electrical signals can be administered intermittently, such that the signal is only actively delivered during portions of the stimulation sessions. In such embodiments, the stimulation session may cycle between "on" times during which the signal is being administered, and "off" times during which the signal is not beingadministered. In some embodiments, the "on" time can be between about 1 second and about 10 minutes, and the "off" time can be between about 1 second and about 10 minutes. Representative examples of suitable intermittent stimulation schedules include 10 seconds on, 10 seconds off; 10 seconds on, 30 seconds off; 10 seconds on, 60 seconds off; 10 seconds on, 90 seconds off; 30 seconds on, 30 seconds off; 30 seconds on, 60 seconds off; 30 seconds on, 90 seconds off; 1 minute on, 1 minute off; 10 minutes on, 10 minutes off, etc. The on times and off times are provided by way of example only — in some embodiments, the electrical signals described herein may be applied according to different on times and off times.

[0041] Regardless of whether the signal is administered intermittently or continuously during the stimulation sessions, the signal can be administered according to a duty cycle of between about 0.1 % and about 100% during each stimulation session. As used herein, and referring again to Figure 2A, the term duty cycle refers to the fraction of a single pulse period 201 (which consists of a single pulse 202 and a single interpulse interval 212) in which the pulse 202 is being actively delivered. That is, for a single pulse period, the duty cycle can be expressed as: (pulse width / duration of pulse period) x 100. For example, if a pulse period comprises (1 ) a bi-phasic pulse with no interphase interval and with each phase of the pulse having a pulse width of 500 microseconds, followed by (2) an interpulse interval having a duration of 99 milliseconds (e.g., before the following pulse period begins), the duty cycle is 1 % (1 millisecond combined pulse width / 100 millisecond pulse period duration, x 100). In this way, the term duty cycle is different than the term intermittent, which generally refers to delivering sequential pulse periods in a row for a first duration (e.g., 10 seconds), followed by a quiescent period during which no pulse periods are delivered for a second duration (e.g., for 90 seconds).C. Timina Discrete Stimulation Sessions to Improve Patient Outcomes

[0042] As set forth above, the electrical signals described herein can be administered during discrete stimulation session or periods, which can have a duration of between about 15 minutes and about 4 hours. Other session lengths or periods can include between about 15 minutes and about 3 hours, or between about 15 minutes and about 2 hours, or between about 30 minutes and about 3 hours, or between about 30 minutes and about 2 hours, or between about 30 minutes and about 1 .5 hours, orbetween about 45 minutes and about 1 .5 hours. In some embodiments, the stimulation sessions can have a duration of about 5 minutes, about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 1 .5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, or about 4 hours. Without intending to be bound by theory, it is expected that timing the delivery of the discrete stimulation sessions to occur during specific patient periods or events may improve the effect the electrical signal has on the patient's IBD symptoms. Accordingly, as described below, the present technology includes systems and methods for timing the delivery of stimulation to coincide with specific periods, events, or patient activities.

[0043] For example, in some embodiments stimulation sessions can be timed to coincide with natural inflammatory and / or natural anti-inflammatory periods in the patient. It is widely accepted that eukaryotic cells have a circadian rhythm or circadian "clock" that causes cells to behave differently at different periods during a 24-hour cycle. Indeed, this circadian clock has been shown to regulate natural and cyclic "pro- inflammatory" and "anti-inflammatory" periods. During pro-inflammatory periods, cells may have an increased tendency to secrete inflammatory cytokines, chemokines, and complement factors. During anti-inflammatory periods, cells may have an increased tendency to secrete anti-inflammatory compounds and / or a decreased tendency to secrete pro-inflammatory compounds. This results in alternating periods throughout the day in which a subject is in a net pro-inflammatory state or a net anti-inflammatory state.

[0044] In some embodiments, the stimulation sessions described above are timed to coincide with natural anti-inflammatory periods. This may boost the natural antiinflammatory state of the patient during these periods. In some patients, the natural antiinflammatory periods occur after sleeping (e.g., in the morning). Accordingly, the systems described herein can be programmed to deliver electrical stimulation in the morning. In some embodiments, the stimulation sessions can be programmed to automatically begin at a certain time of day that is around a normal wake time for a given patient. Wake times for individual patients can be determined based on patient questionnaires and journals. Representative start times include, but are not limited to 5:00 AM, 5:30 AM, 6:00 AM, 6:30AM, 7:00AM, 7:30AM, 8:00 AM, 8:30AM, or 9:00AM.

[0045] In other embodiments, the stimulation sessions described above can be timed to coincide with natural pro-inflammatory periods, e.g., to mitigate theinflammatory effect these periods have on the patient's IBD. In some patients, the inflammatory period occurs in the afternoon. Accordingly, the systems described herein can be programmed to deliver electrical stimulation in the afternoon. In some embodiments, the stimulation sessions can be programmed to automatically begin at a certain time of day that typically coincides with the pro-inflammatory periods. Representative start times include, but are not limited to, 1 :00PM, 2:00PM, 3:00PM, 4:00PM, and / or 5:00PM.

[0046] In some embodiments, the stimulation sessions can be timed to coincide with both natural anti-inflammatory periods and natural pro-inflammatory periods as each occurs throughout the day. For example, one stimulation session can start during an anti-inflammatory period (e.g., the morning) and last for 15 minutes to 4 hours, and then a second stimulation session can start during a pro-inflammatory period (e.g., the afternoon or evening) and last for 15 minutes to 4 hours.

[0047] Instead of being programmed to begin at a specific time of day as described above, the systems described herein can alternatively be programmed to automatically initiate stimulation in response to detecting a wake state in the patient, and / or a defined period of time after detecting a wake state (e.g., immediately upon waking, 30 minutes after waking, 1 hour after waking, 1 .5 hours after waking, etc.). In such embodiments, the systems described herein can include one or more sensors (such as the sensor 115 of the system 100 described with reference to Figure 1 ) that can detect a sleep / wake state of the patient. Representative sensors include, but are not limited to, a heart rate sensor, a respiratory rate sensor, a blood oxygenation sensor, an accelerometer, a gyroscope, and the like.

[0048] The systems and methods described herein can also measure or otherwise track one or more physiological parameters to determine when to administer the stimulation session. For example, core body temperature typically follows a predictable circadian pattern over the course of a 24-hour period, with fluctuations in core temperature tracking changes in a patient's inflammatory state. For example, increased core temperature generally indicates increased inflammation, and decreased core temperature generally indicates decreased inflammation. Accordingly, core body temperature can be tracked, and stimulation can be delivered in response to core body temperature meeting one or more prescribed thresholds. Core body temperature canbe measured using a thermocouple, thermistor, or other temperature sensor contained within an implanted component of the sacral neuromodulation system (e.g., such as the sensor 1 15 of the system 100, described with reference to Figure 1A), contained within an implanted component separate from the sacral neuromodulation system, and / or contained within a wearable device.

[0049] In some embodiments, the system can be programmed to automatically initiate stimulation in response to detecting an increase in core temperature above a defined threshold (e.g., an increase of 0.3°C, 0.4°C, 0.5°C, 0.6°C, 0.7°C, 0.8°C, 0.9°C, 1.0°C, etc., relative to a baseline temperature; the baseline temperature can represent an average body temperature over a 24 hour or other period). Because core temperature and inflammatory periods are linked, this would generally result in stimulation being delivered during naturally pro-inflammatory periods. Alternatively, the system can be programmed to automatically initiate stimulation in response to detecting a decrease in core temperature below a defined threshold (e.g., a decrease of 0.3°C, 0.4°C, 0.5°C, 0.6°C, 0.7°C, 0.8°C, 0.9°C, 1.0°C, etc., relative to the baseline temperature). This would generally result in stimulation being delivered during naturally anti-inflammatory periods. In addition to controlling a timing of stimulation, core temperature could also be utilized to automatically adjust an intensity (e.g., amplitude) of stimulation. In such embodiments, stimulation intensity can be automatically increased in response to an increase in core temperature and automatically decreased in response to a decrease in core temperature.

[0050] Physiological parameters other than core temperature can also be used to control a timing and / or intensity of stimulation. For example, the sacral neuromodulation systems described herein could include one or more sensors for detecting inflammatory biomarkers, such as pro-inflammatory cytokines, chemokines, or other molecules. The signal generator can be programmed to automatically initiate stimulation, and / or automatically increase an intensity of stimulation, in response to detecting an increase in an inflammatory biomarker above a predefined threshold or concentration. The signal generator can also be programmed to automatically terminate stimulation, and / or automatically decrease an intensity of stimulation, in response to detecting a decrease in the inflammatory biomarker.

[0051] Another example physiological parameter that can be tracked to control a timing and / or intensity of stimulation is heart rate and / or heart rate variability. Heart rate variability refers to fluctuations in the duration between subsequent heart beats, and includes a low-frequency component (e.g., <0.10 Hz) and a high-frequency component (e.g., >0.20Hz). The high frequency component of heart rate variability can be used an indicator of parasympathetic nervous system activity, while the ratio of the low frequency component and the high frequency component can be used as an indicator of sympathetic nervous system activity. Thus, heart rate variability can be used to monitor a balance between a patient's sympathetic and parasympathetic nervous systems. Accordingly, heart rate variability and related metrics (e.g., ratio derived from heart rate variability) can be used to control a timing or, and / or an intensity of, stimulation.

[0052] The timing of the stimulation sessions can be based on other patient activities or events besides an inflammatory state of the patient. For example, in some embodiments the system is programmed to deliver the stimulation session while the patient is asleep. Similar to described above, this can be accomplished by (a) programming the system to automatically deliver the stimulation session at a time in which the patient is generally asleep (e.g., at 1 :00AM, at 2:00AM, etc.), and / or (b) programming the system to automatically deliver the stimulation session in response to detecting one or more sensed parameters that indicate the patient is asleep. Suitable sensed parameters that can be used to determine if the patient is in a sleep or wake state include, but are not limited to, heart rate, heart rate variability, core temperature, and other physiological parameters described above. Additional sensed parameters that can be used to determine if the patient is in a sleep or wake state include motion sensors, such as an accelerometer, a gyroscope, or the like, and / or impedance monitors that can detect changes in impedance between electrodes on the signal delivery device. As described above, such sensors can be included in the implanted neuromodulation system (e.g., such as the sensor 115 of the system 100, described with reference to Figure 1A), implanted separate from the implanted neuromodulation system, and / or included on a wearable or other external device.

[0053] Without intending to be bound by theory, administering the electrical stimulation while the patient is asleep may provide several therapeutic benefits. First, the electrical stimulation may improve the patient's quality of sleep by directly reducinggastrointestinal distress, pain, and / or other IBD symptoms that may interfere with the patient's ability to sleep. Second, the stimulation may boost the patient's natural antiinflammatory state by enabling the patient to have better quality sleep, which as set forth above generally induces a natural anti-inflammatory state in patients.

[0054] In some embodiments, the neuromodulation systems described herein are programmed to deliver the stimulation sessions immediately before, during, or immediately after a patient is prandial. In such embodiments, the signal generator can be programmed to automatically deliver a stimulation session every day at times that generally coincide with a patient consuming food. For example, the signal generator can be programmed to automatically deliver a first stimulation session at 8AM, a second stimulation session at 12PM, and / or a third stimulation session at 6PM. Alternatively, the system can be programmed to automatically deliver a stimulation session in response to detecting one or more physiological parameters that indicate the patient is prandial. Representative parameters include blood glucose level, insulin level, leptin serum concentration, ghrelin serum concentration, or the like.

[0055] Accordingly, as set forth above, the present technology includes closed- loop feedback methods for delivering sacral nerve stimulation that are based on one or more sensed parameters. Figure 3 is a flowchart of a representative method 300 of delivering closed-loop sacral nerve stimulation to treat IBD in accordance with embodiments of the present technology. The method 300 can begin at block 302 by monitoring or measuring one or more physiological parameters of the patient. The physiological parameters can include any of the physiological parameters described herein, such as patient sleep / wake state, patient movement, core temperature, heart rate, heart rate variability, inflammatory markers, blood glucose level, insulin level, leptin serum concentration, ghrelin serum concentration, or the like. In some embodiments, the one or more physiological parameters may be associated with or indicative of one or more of an inflammatory state of the patient, a sleep / wake state of the patient, and / or whether the patient is prandial. The physiological parameter can be monitored via one or more sensors that can be implanted with the signal generator, implanted but spaced apart from the signal generator, or external to the patient.

[0056] The method 300 can continue at block 304 by comparing the one or more measured physiological parameters to a predetermined threshold. The predeterminedthreshold can be set based on a known association between the physiological parameter and a patient condition or state. For example, if the physiological parameter is core temperature, the predetermined threshold can be a core temperature that indicates the patient is in a pro-inflammatory state. Thus, the predetermined threshold could be a core temperature value that is 0.3°C, 0.4°C, 0.5°C, 0.6°C, 0.7°C, 0.8°C, 0.9°C, or 1 ,0°C greater than a relative baseline temperature. Similarly, if the predetermined threshold is core temperature that indicates the patient is in an antiinflammatory state, the predetermined threshold could be a core temperature value that is 0.3°C, 0.4°C, 0.5°C, 0.6°C, 0.7°C, 0.8°C, 0.9°C, or 1 .0°C less than a relative baseline temperature. As another example, if the physiological parameter is leptin serum level, the predetermined threshold could be set to a leptin serum concentration that is consistent with the patient being prandial.

[0057] Regardless of the specific parameter or threshold used at blocks 302 and 304, the method 300 continues at block 304 by, in response to determining that the one or more measured physiological parameters meet the predetermined threshold, automatically delivering an electrical signal to a sacral nerve of the patient for a predetermined duration. The electrical signal can have any of the signal delivery parameters described above in Section B of this Detailed Description. The predetermined duration can be any duration described with respect to the discrete stimulation sessions described throughout this Detailed Description, such as between about 15 minutes and about 4 hours.

[0058] As one skilled in the art will appreciate, the method 300 can operate in a closed-loop format. That is, the operations of measuring, comparing, and delivering can be automatically performed by a programmed neuromodulation system, such as the system 100 described with reference to FIGS. 1 A and 1 B. Accordingly, the present technology further includes programming a system to perform the operations of the method 300 and systems programmed to perform the operations of the method 300.

[0059] Moreover, even though some of the embodiments described above include automatically delivering stimulation in response to certain physiological conditions occurring (e.g., inflammatory states, sleep / wake cycle, etc.), the systems described herein can be programmed to further include a minimum and a maximum number of stimulation sessions (and / or a minimum and maximum duration of stimulation) that theclosed-loop feedback techniques operate within. For example, the system can be programmed to ensure that a patient receives at least a minimum amount of stimulation (e.g., 1 hour of stimulation) per day, regardless of whether the tracked physiological parameter meets a particular threshold for initiating stimulation. This ensures that the patient receives a minimum dose of stimulation each day. Similarly, the system can be programmed not to exceed a total amount of stimulation per day (e.g., not to exceed 4 hours of total stimulation per day). This ensures that the patient is not "overstimulated," which can potentially lead to neural adaptation or habituation.

[0060] In some embodiments, a patient can have at least partial control over the number, timing, and / or intensity of the stimulation sessions. For example, a patient may be able to initiate a stimulation session using a patient controller (e.g., "on-demand" stimulation session). This enables a patient to initiate therapy in situations in which the patient typically experiences an increase in IBD symptoms, such as periods of travel, increased stress, illness, anxiety, depression, or the like. In such embodiments, the patient may also be receiving stimulation according to a feedback loop such as those described above. Accordingly, the number of stimulation sessions may still be confined within a prescribed number of daily or weekly stimulation sessions such that the patient cannot inadvertently overstimulate themselves.

[0061] In addition to initiating an on-demand stimulation sessions, a patient can also use the patient controller to schedule a stimulation session to occur at a future date and time. For example, if the patient knows that they will be traveling aboard an airplane that departs at 2:00PM on Tuesday and has a personal history of increased symptoms while traveling, the patient can schedule a stimulation session to begin at, e.g., 1 :30PM on the Tuesday. In some embodiments, stimulation sessions can be scheduled up to 5, 6, 7, 8, 9, ten, or more days in advance. Additionally, if the patient has a life event that occurs on a repetitive schedule and that is associated with increased symptoms, the patient can also schedule stimulation sessions to automatically occur during those events (e.g., a stimulation session is automatically initiated every Monday morning at 11 :00AM to coincide with a stressful recurring work event that causes a consistent increase in patient symptoms).

[0062] Although described as initiating and / or scheduling stimulation sessions, a patient may also at least partially control the stimulation intensity. For example, a patientcan prophylactically increase the stimulation intensity, or schedule a prophylactic increase in stimulation intensity, in response to known upcoming events that typically cause worse symptoms. Without intending to be bound by theory, giving the patient control over the timing and intensity of the stimulation sessions may reduce the severity and / or occurrence of symptom flare ups during life events that typically cause worse symptoms in the patient.D. Geofencinq

[0063] In addition to or in lieu of timing the stimulation sessions to coincide with particular patient events or states, in some embodiments the stimulation sessions can be predicated based upon the patient occupying specific locations. Some patients may prefer the stimulation sessions to occur while the patient is at home and not occur while the patient is at work. This may be particularly true if the stimulation is above the sensory threshold and the patient can perceive the stimulation as it is being delivered. To some patients, such sensation may be distracting while they are at work or otherwise occupied. Accordingly, some patients may prefer to receive the stimulation sessions when they are at a specific location amendable to stimulation, such as at their house.

[0064] In such embodiments, the systems can include or otherwise be in communication with a global positioning system ("GPS") or other location tracker. The GPS can be incorporated into the sacral neuromodulation system itself, such as the sensor 1 15 of the signal generator 110 of the system 100 described with reference to Figure 1 . In other embodiments, the GPS can be incorporated into a separate component that communicates with the sacral neuromodulation system. For example, the GPS can be included in a wearable component (e.g., a smart watch) that communicates with either the signal generator or the system controller. As another example, the patient's mobile phone GPS could be used to track a location of the patient and transmit the location to the signal generator and / or the system controller. In such embodiments, the GPS device can communicate with the system via Bluetooth, cellular, near-field communication, WiFi, or other suitable communication modalities.

[0065] In some embodiments, a user (e.g., a patient or physician) can specify one or more geographic areas in which they wish to stimulation to be administered. This could be done using the system controller or via a separate application installed on another user device (e.g., a user's smart phone, a clinician's laptop, etc.). For example,the user could define (e.g., draw, select, color, etc.) one or more stimulation zones on a map displayed by the system controller or other application. In some embodiments, the system can then convert the selected regions into geographic coordinates that define boundaries for one or more stimulation zones. Alternatively or additionally, the user can input an address (e.g., a street address) into the system controller or other application and ascribe the address to a specific category, such as "home," "work," or "gym." Similarly, the user can specify one or more geographic areas in which they do not want stimulation to be administered. This could be done using the same input methods described above, but with the additional step of specifying the inputted areas are no stimulation zones.

[0066] The stimulation zones and no stimulation zones therefore correspond to different geographic locations or addresses. For example, a user could define that stimulation should only be administered when the system determines the patient is at home, and that stimulation should not be administered when the system determines the patient is at work. However, the stimulation zones and no stimulation zones can also be more specific. For example, a user could define that stimulation should be administered when the system determines the patient is in a first room at home (e.g., the bedroom) but not in a second room at home (e.g., a kitchen). As one skilled in the art will appreciate, the foregoing are provided by way of example only — a user can define any geographic area or any size as a stimulation zone or as a no stimulation zone.

[0067] Figure 4 is a flowchart of a method 400 of delivering sacral nerve stimulation to treat IBD based on geofencing and in accordance with embodiments of the present technology. The method 400 can begin at block 402 by determining a patient is due for a stimulation session. In some embodiments, this can be done by determining the number of stimulation sessions the patient has received over a preceding period (e.g., the number of stimulation sessions the patient has received in the preceding 24 hours). As described throughout this Detailed Description, a physician may prescribe a patient to receive a specified number of discrete stimulation sessions over a defined period. This could include, for example, one, two, three, four, or more discrete stimulation sessions per day. As set forth above, the discrete stimulation sessions can have a duration of between about 15 minutes and about 4 hours, although other durations are possible and within the scope of the present technology.Accordingly, the operation at block 402 can determine whether a patient is due to receive a stimulation session.

[0068] The method 400 can continue at block 404 by monitoring a location of a patient. In some embodiments, the operation at block 404 is performed in response to determining that the patient is due for a stimulation session at block 402. In other embodiments, the operation at block 404 can be performed independently of the operation at block 404. Regardless, the location of the patient can be monitored using a GPS or other location tracking device. As set forth above, the GPS or other location tracker can be part of the sacral neuromodulation system, and / or can be included in a separate device (e.g., smart watch, patient mobile phone, etc.) that communicates with the implanted sacral neuromodulation system.

[0069] The method 400 can continue at block 406 by determining whether the patient is in a defined stimulation zone. A defined stimulation zone is a geographic area designated by a user as being an acceptable location to receive stimulation. For as example, as described above, a user (e.g., the physician or patient) can set stimulation zones using a map or other user interface. If the GPS location is within the defined stimulation zone, the method 400 can continue at block 408 by initiating the stimulation session. Accordingly, the operation at block 408 can include administering an electrical signal to the patient's sacral nerve to treat the patient's IBD.

[0070] If at block 406 the GPS location is not within a defined stimulation zone, and / or is within a no stimulation zone, the method 400 can proceed at block 410 by determining whether a predefined amount of time has elapsed since the patient's previous stimulation session. The predefined amount of time can be set based on a maximum duration between subsequent stimulation sessions that should not be exceeded. The duration may depend on the number of stimulation sessions the patient receives per day, the duration of individual stimulation sessions, the severity of the patient symptoms, and / or other parameters. Example durations include 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, and 16 hours.

[0071] If at block 408 the predefined amount of time has not elapsed, the method 400 can return to block 404 and monitor a location of the patient. This may include continuously or periodically monitoring the location of the patient. The operations at block 404, 406, and 410 can then be repeated until the patient is within a definedstimulation zone, at which point the method 400 can proceed to block 408 and begin the stimulation session.

[0072] If, however, at block 410 the predefined amount of time has elapsed since the patient's previous stimulation session, the method 400 can continue at block 412 by providing an alert to the user that a stimulation session is overdue. The alert can be displayed on the patient programmer, the patient's mobile phone, or via another suitable device. In response to the alert, the patient can go to a defined stimulation zone to receive the stimulation session or initiate a stimulation session at their current location, even if it is not in a defined stimulation zone. Without intending to be bound by theory, the operations at blocks 410 and 412 are expected to reduce the likelihood that the patient does not receive enough therapy in the event the patient does not occupy a defined stimulation zone for a prolonged period.

[0073] As one skilled in the art will appreciate, some or all of the operations described with reference to the method 400 can operate in a closed-loop format. That is, any combination of the operations of determining a patient is due for a stimulation session (block 402), monitoring a location of a patient (block 404), determining if the patient is in a defined stimulation zone (block 406), beginning stimulation (block 408), determining if a predefined amount of time has elapsed since the patient's previous stimulation session (block 410), and providing an alert to the user (block 412) can be automatically performed by a programmed neuromodulation system, such as the system 100 described with reference to FIGS. 1 A and 1 B. Accordingly, the present technology further includes programming a system to perform the operations of the method 400 and systems programmed to perform the operations of the method 400.E. Representative Examples

[0074] The following examples are provided to further illustrate embodiments of the present technology and are not to be interpreted as limiting the scope of the present technology. To the extent that certain embodiments or features thereof are mentioned, it is merely for purposes of illustration and, unless otherwise specified, is not intended to limit the present technology. It will be understood that many variations can be made in the procedures described herein while still remaining within the bounds of the present technology. Such variations are intended to be included within the scope of the presently disclosed technology.1. A method of using sacral nerve stimulation to treat a patient with Inflammatory Bowel Disease (IBD), the method comprising: determining the patient is due for a sacral nerve stimulation session, wherein the stimulation session has a duration of between about 15 minutes and about 4 hours; determining a location of the patient; if the patient is in one of one or more defined stimulation zones, automatically initiating the stimulation session, wherein initiating the stimulation session includes delivering an electrical signal to a sacral nerve of the patient via an implanted signal delivery device; and if the patient is not in one of the one or more defined stimulation zones, monitoring the location of the patient until the patient is in one of the one or more defined stimulation zones.2. The method of example 1 wherein the one or more defined stimulation zones correspond to specific geographic areas.3. The method of example 2 wherein the specific geographic areas include one or more boundaries defined by geographic coordinates.4. The method of example 2 wherein the specific geographic areas include one or more street addresses.5. The method of any of examples 1 -4 wherein determining the patient is due for a sacral nerve stimulation session includes comparing a number of stimulation sessions administered over a preceding period to a number of stimulation sessions prescribed to be administered over the preceding period.6. The method of any of examples 1 -5 wherein determining the location of the patient includes using a GPS device to determine a geographic location of the patient.7. The method of example 6 wherein the GPS device is implanted in the patient.8. The method of any of examples 1 -7, further comprising: in response to determining the patient is not in one of the one or more defined stimulation zones, determining whether a predefined amount of time has elapsed since the patient's previous stimulation session; if the predefined amount of time has not elapsed, continuing to monitor the location of the patient until the patient is in one of the one or more defined stimulation zones; and if the predefined amount of time has elapsed, providing an alert notifying the patient that a stimulation session is overdue.9. A system for treating a patient with Inflammatory Bowel Disease (IBD), the system comprising: an implantable signal delivery device positionable proximate a sacral nerve of the patient; a signal generator programmed with instructions that, when executed, cause the signal generator to generate an electrical signal and deliver the electrical signal to the sacral nerve of the patient, via the implantable signal delivery device, in a stimulation session having a duration of between about 15 minutes and about 4 hours; and a location monitoring device configured to determine a location of the patient, wherein the system is configured to — determine the patient is due for the stimulation session, in response to determining the patient is due for the stimulation session, determine the location of the patient, if the patient is in one of one or more defined stimulation zones, automatically initiating the stimulation session, and if the patient is not in one of the one or more defined stimulation zones, monitoring the location of the patient until the patient is in one of the one or more defined stimulation zones.10. The system of example 9 wherein the location monitoring device is a GPS device.1 1 . The system of example 9 or example 10 wherein the location monitoring device positioned within or physically coupled to the signal generator.12. The system of any of examples 9-11 wherein the one or more defined stimulation zones correspond to specific geographic areas.13. The system of example 12 wherein the specific geographic areas include one or more boundaries defined by geographic coordinates.14. The system of example 12 wherein the specific geographic areas include one or more street addresses.15. The system of any of examples 9-14 wherein the operation of determining the patient is due for the stimulation session includes comparing a number of stimulation sessions administered over a preceding period to a number of stimulation sessions prescribed to be administered over the preceding period.16. The system of any of examples 9-15, wherein the system is further configured to: in response to determining the patient is not in one of the one or more defined stimulation zones, determine whether a predefined amount of time has elapsed since the patient's previous stimulation session; if the predefined amount of time has not elapsed, continue to monitor the location of the patient until the patient is in one of the one or more defined stimulation zones; and if the predefined amount of time has elapsed, provide an alert notifying the patient that a stimulation session is overdue.17. The system of any of examples 9-16 wherein the electrical signal has a frequency within a frequency range of from about 1 Hz to about 10 Hz.18. The system of any of examples 9-17 wherein the electrical signal has a frequency within a frequency range of from about 4 Hz to about 6 Hz.19. A method of using sacral nerve stimulation to treat a patient with Inflammatory Bowel Disease (IEBD), the method comprising: measuring, via one or more sensors, a physiological parameter of the patient associated with an inflammatory state of the patient; comparing the measured physiological parameter of the patient to a predetermined threshold; and in response to determining the measured physiological parameter meets the predetermined threshold, automatically delivering an electrical signal to a sacral nerve of the patient, wherein the electrical signal is delivered in accordance with a stimulation session having a predetermined duration of between about 15 minutes and about 4 hours.20. The method of example 19 wherein the physiological parameter includes body temperature, heart rate, heart rate variability, and / or an inflammatory biomarker.21. The method of example 19 or example 20 wherein the predetermined threshold is associated with the patient being in a pro-inflammatory state such that the electrical signal is automatically delivered in response to detecting that the patient has entered a pro-inflammatory state.22. The method of example 21 wherein the physiological parameter is body temperature, and wherein the predetermined threshold is a threshold temperature value greater than a baseline body temperature by a specific amount.23. The method of example 22 wherein the specific amount is between 0.3°C and 1 .0°C.24. The method of example 19 or example 20 wherein the predetermined threshold is associated with the patient being in an anti-inflammatory state such that theelectrical signal is automatically delivered in response to detecting that the patient has entered an anti-inflammatory state.25. The method of example 24 wherein the physiological parameter is body temperature, and wherein the predetermined threshold is a threshold temperature value less than a baseline body temperature by a specific amount.26. The method of example 25 wherein the specific amount is between 0.3°C and 1 ,0°C.27. The method of any of examples 19-26, further comprising: receiving a request from the patient to initiate a stimulation session during a period in which the measured physiological parameter does not meet the predetermined threshold; and in response to receiving the request, delivering the electrical signal to the sacral nerve of the patient in accordance with an on-demand stimulation session.28. The method of example 27 wherein the request is to initiate the stimulation session at a future date and time, and wherein delivering the electrical signal includes delivering the electrical signal at the future date and time.29. A system for treating a patient with Inflammatory Bowel Disease (IBD), the system comprising: a sensor configured to measure a physiological parameter of the patient that is associated with an inflammatory state of the patient; an implantable signal delivery device positionable proximate a sacral nerve of the patient; and a signal generator programmed with instructions that, when executed, cause the signal generator to generate an electrical signal and deliver the electrical signal to the sacral nerve of the patient, via the implantable signal delivery device, in a stimulation session having a duration of between about 15 minutes and about 4 hours, wherein the system is configured to —measure, via the sensor, the physiological parameter, compare the measured physiological parameter to a predetermined threshold, and in response to determining the measured physiological parameter meets the predetermined threshold, automatically initiate the stimulation session.30. The system of claim 29 wherein the sensor is configured to measure body temperature, heart rate, heart rate variability, and / or an inflammatory biomarker.31 . The system of example 29 or example 30 wherein the predetermined threshold is associated with the patient being in a pro-inflammatory state such that the electrical signal is automatically delivered in response to detecting that the patient has entered a pro-inflammatory state.32. The system of example 31 wherein the physiological parameter is body temperature, and wherein the predetermined threshold is a threshold temperature value greater than a baseline body temperature by a specific amount.33. The system of example 32 wherein the specific amount is between 0.3°C and 1 .0°C.34. The system of example 29 or example 30 wherein the predetermined threshold is associated with the patient being in an anti-inflammatory state such that the electrical signal is automatically delivered in response to detecting that the patient has entered an anti-inflammatory state.35. The system of example 34 wherein the physiological parameter is body temperature, and wherein the predetermined threshold is a threshold temperature value less than a baseline body temperature by a specific amount.36. The system of example 35 wherein the specific amount is between 0.3°C and 1 .0°C.F. Conclusion

[0075] From the foregoing, it will be appreciated that specific embodiments of the disclosed technology have been described herein for purposes of illustration, but that various modifications may be made without deviating from the technology. For example, electrical signals described herein can be delivered at combinations of parameter values within the foregoing ranges at values that are not expressly disclosed herein. Certain aspects of the technology described in the context of particular embodiments may be combined or eliminated in other embodiments. Further, while advantages associated with certain embodiments of the disclosed technology have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the present technology. Accordingly, the disclosure and associated technology can encompass other embodiments not expressly shown or described herein.

[0076] The use of "and / or," as in "A and / or B" refers to A alone, B alone, and both A and B. Additionally, the term "comprising" is used throughout to mean including at least the recited feature(s) such that any greater number of the same feature and / or additional types of other features are not precluded. It will also be appreciated that specific embodiments have been described herein for purposes of illustration, but that various modifications may be made without deviating from the technology. Further, while advantages associated with certain embodiments of the technology have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the technology. Accordingly, the disclosure and associated technology can encompass other embodiments not expressly shown or described herein.

[0077] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, to between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges mayindependently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

Claims

CLAIMSI / We claim:

1. A method of using sacral nerve stimulation to treat a patient with Inflammatory Bowel Disease (IBD), the method comprising: determining the patient is due for a sacral nerve stimulation session, wherein the stimulation session has a duration of between about 15 minutes and about 4 hours; determining a location of the patient; if the patient is in one of one or more defined stimulation zones, automatically initiating the stimulation session, wherein initiating the stimulation session includes delivering an electrical signal to a sacral nerve of the patient via an implanted signal delivery device; and if the patient is not in one of the one or more defined stimulation zones, monitoring the location of the patient until the patient is in one of the one or more defined stimulation zones.

2. The method of claim 1 wherein the one or more defined stimulation zones correspond to specific geographic areas.

3. The method of claim 2 wherein the specific geographic areas include one or more boundaries defined by geographic coordinates.

4. The method of claim 2 wherein the specific geographic areas include one or more street addresses.

5. The method of claim 1 wherein determining the patient is due for a sacral nerve stimulation session includes comparing a number of stimulation sessions administered over a preceding period to a number of stimulation sessions prescribed to be administered over the preceding period.

6. The method of claim 1 wherein determining the location of the patient includes using a GPS device to determine a geographic location of the patient.

7. The method of claim 6 wherein the GPS device is implanted in the patient.

8. The method of claim 1 , further comprising: in response to determining the patient is not in one of the one or more defined stimulation zones, determining whether a predefined amount of time has elapsed since the patient's previous stimulation session; if the predefined amount of time has not elapsed, continuing to monitor the location of the patient until the patient is in one of the one or more defined stimulation zones; and if the predefined amount of time has elapsed, providing an alert notifying the patient that a stimulation session is overdue.

9. A system for treating a patient with Inflammatory Bowel Disease (IBD), the system comprising: an implantable signal delivery device positionable proximate a sacral nerve of the patient; a signal generator programmed with instructions that, when executed, cause the signal generator to generate an electrical signal and deliver the electrical signal to the sacral nerve of the patient, via the implantable signal delivery device, in a stimulation session having a duration of between about 15 minutes and about 4 hours; and a location monitoring device configured to determine a location of the patient, wherein the system is configured to — determine the patient is due for the stimulation session, in response to determining the patient is due for the stimulation session, determine the location of the patient, if the patient is in one of one or more defined stimulation zones, automatically initiating the stimulation session, andif the patient is not in one of the one or more defined stimulation zones, monitoring the location of the patient until the patient is in one of the one or more defined stimulation zones.

10. The system of claim 9 wherein the location monitoring device is a GPS device.1 1 . The system of claim 9 or claim 10 wherein the location monitoring device positioned within or physically coupled to the signal generator.

12. The system of claim 9 wherein the one or more defined stimulation zones correspond to specific geographic areas.

13. The system of claim 12 wherein the specific geographic areas include one or more boundaries defined by geographic coordinates.

14. The system of claim 12 wherein the specific geographic areas include one or more street addresses.

15. The system of claim 9 wherein the operation of determining the patient is due for the stimulation session includes comparing a number of stimulation sessions administered over a preceding period to a number of stimulation sessions prescribed to be administered over the preceding period.

16. The system of claim 9, wherein the system is further configured to: in response to determining the patient is not in one of the one or more defined stimulation zones, determine whether a predefined amount of time has elapsed since the patient's previous stimulation session; if the predefined amount of time has not elapsed, continue to monitor the location of the patient until the patient is in one of the one or more defined stimulation zones; and if the predefined amount of time has elapsed, provide an alert notifying the patient that a stimulation session is overdue.

17. The system of claim 9 wherein the electrical signal has a frequency within a frequency range of from about 1 Hz to about 10 Hz.

18. The system of claim 9 wherein the electrical signal has a frequency within a frequency range of from about 4 Hz to about 6 Hz.

19. A method of using sacral nerve stimulation to treat a patient with Inflammatory Bowel Disease (IBD), the method comprising: measuring, via one or more sensors, a physiological parameter of the patient associated with an inflammatory state of the patient; comparing the measured physiological parameter of the patient to a predetermined threshold; and in response to determining the measured physiological parameter meets the predetermined threshold, automatically delivering an electrical signal to a sacral nerve of the patient, wherein the electrical signal is delivered in accordance with a stimulation session having a predetermined duration of between about 15 minutes and about 4 hours.

20. The method of claim 19 wherein the physiological parameter includes body temperature, heart rate, heart rate variability, and / or an inflammatory biomarker.

21. The method of claim 19 wherein the predetermined threshold is associated with the patient being in a pro-inflammatory state such that the electrical signal is automatically delivered in response to detecting that the patient has entered a pro-inflammatory state.

22. The method of claim 21 wherein the physiological parameter is body temperature, and wherein the predetermined threshold is a threshold temperature value greater than a baseline body temperature by a specific amount.

23. The method of claim 22 wherein the specific amount is between 0.3°C and 1 .0°C.

24. The method of claim 19 wherein the predetermined threshold is associated with the patient being in an anti-inflammatory state such that the electrical signal is automatically delivered in response to detecting that the patient has entered an anti-inflammatory state.

25. The method of claim 24 wherein the physiological parameter is body temperature, and wherein the predetermined threshold is a threshold temperature value less than a baseline body temperature by a specific amount.

26. The method of claim 25 wherein the specific amount is between 0.3°C and 1 .0°C.

27. The method of claim 19, further comprising: receiving a request from the patient to initiate a stimulation session during a period in which the measured physiological parameter does not meet the predetermined threshold; and in response to receiving the request, delivering the electrical signal to the sacral nerve of the patient in accordance with an on-demand stimulation session.

28. The method of claim 27 wherein the request is to initiate the stimulation session at a future date and time, and wherein delivering the electrical signal includes delivering the electrical signal at the future date and time.

29. A system for treating a patient with Inflammatory Bowel Disease (IBD), the system comprising: a sensor configured to measure a physiological parameter of the patient that is associated with an inflammatory state of the patient; an implantable signal delivery device positionable proximate a sacral nerve of the patient; and a signal generator programmed with instructions that, when executed, cause the signal generator to generate an electrical signal and deliver the electrical signal to the sacral nerve of the patient, via the implantable signal deliverydevice, in a stimulation session having a duration of between about 15 minutes and about 4 hours, wherein the system is configured to — measure, via the sensor, the physiological parameter, compare the measured physiological parameter to a predetermined threshold, and in response to determining the measured physiological parameter meets the predetermined threshold, automatically initiate the stimulation session.

30. The system of claim 29 wherein the sensor is configured to measure body temperature, heart rate, heart rate variability, and / or an inflammatory biomarker.31 . The system of claim 29 wherein the predetermined threshold is associated with the patient being in a pro-inflammatory state such that the electrical signal is automatically delivered in response to detecting that the patient has entered a pro-inflammatory state.

32. The system of claim 31 wherein the physiological parameter is body temperature, and wherein the predetermined threshold is a threshold temperature value greater than a baseline body temperature by a specific amount.

33. The system of claim 32 wherein the specific amount is between 0.3°C and 1.0°C.

34. The system of claim 29 wherein the predetermined threshold is associated with the patient being in an anti-inflammatory state such that the electrical signal is automatically delivered in response to detecting that the patient has entered an anti-inflammatory state.

35. The system of claim 34 wherein the physiological parameter is body temperature, and wherein the predetermined threshold is a threshold temperature value less than a baseline body temperature by a specific amount.

36. The system of claim 35 wherein the specific amount is between 0.3°C and1.0°C.

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