Systems and methods for treating inflammatory bowel disease using 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 a signal delivery device positioned proximate one or more of the patient's sacral nerves. In some embodiments, the electrical signal can modulate neural activity in the patient, which may in turn reduce inflammation in the patient by altering an imbalance between the patient's sympathetic nervous system and parasympathetic nervous system, and / or modifying a threshold for an inflammatory response in the gastrointestinal system.

Description

SYSTEMS AND METHODS FOR TREATING INFLAMMATORYBOWEL DISEASE USING SACRAL NEUROMODULATIONCROSS-REFERENCE TO RELATED APPLICATION(S)

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 656,522, filed June 5, 2024, 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, bowel urgency, bowel frequency, and fecal incontinence), and other complications (e.g., rectal bleeding, 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 urge incontinence, urgency frequency, 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 an embodiment of the sacral neuromodulation system of Figure 1 with multiple signal delivery devices for providing bilateral sacral stimulation and configured in accordance with some embodiments of the present technology.

[0007] Figure 1 C illustrates another embodiment of the sacral neuromodulation system of Figure 1 A with multiple signal delivery devices for stimulating different target structures and configured in accordance with some embodiments of the present technology.

[0008] Figure 1 D illustrates two sacral neuromodulation systems implanted at a patient’s sacral region to independently deliver electrical signals and configured in accordance with some embodiments of the present technology.

[0009] Figure 1 E illustrates sacral nerve anatomy of a patient, along with a portion of a signal delivery device of the system of Figures 1A-1 D shown as implanted at a representative location in accordance with some embodiments of the present technology.

[0010] Figure 2A is a partially schematic illustration of an electrical signal generated in accordance with some embodiments of the present technology.

[0011] Figure 2B is a partially schematic illustration of another electrical signal generated in accordance with some embodiments of the present technology.

[0012] Figure 3 is a partially schematic illustration of a transcutaneous sacral neuromodulation system positioned at a patient’s sacral region to deliver electrical signals in accordance with some embodiments of the present technology.

[0013] Figure 4 is a flowchart of a method for identifying an effective sacral nerve stimulation recipe for treating IBD in accordance with embodiments of the present technology.

[0014] Figure 5A is a graph depicting results of an animal study examining the use of sacral nerve stimulation to treat IBD in accordance with embodiments of the present technology.

[0015] Figure 5B is another graph depicting results of the animal study examining the use of sacral nerve stimulation to treat IBD in accordance with embodiments of the present technology.

[0016] Figure 6A is a graph depicting results of a human pilot study examining the use of sacral nerve stimulation to treat a first cohort of patients with ulcerative colitis in accordance with embodiments of the present technology.

[0017] Figure 6B is a graph depicting results of the human pilot study examining the use of sacral nerve stimulation to treat a second cohort of patients with Crohn’s disease in accordance with embodiments of the present technology.

[0018] Figure 7A is a graph depicting improvement in bowel urgency for both the first and second cohort of patients included in the human pilot study.

[0019] Figure 7B is a graph depicting improvement in bowel urgency for the first cohort of patients.

[0020] Figure 7C is a graph depicting improvement in bowel urgency for the second cohort of patients.DETAILED DESCRIPTIONA. Introduction

[0021] 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 electrical signal can be delivered via a signal delivery device positioned proximate one or more of the patient’s sacral nerves. The electrical signal can modulate the activity of the sacral nerve(s) and / or other nerves, which may in turn reduce inflammation in the patient by altering an imbalance between the patient’s sympathetic nervous system and parasympathetic nervous system and / or modifying a threshold for an inflammatory response in the gastrointestinal system. Without being bound by theory, it is expected that delivering electrical signals to the patient’s sacral nerve in accordance with the present technology may induce fewer side effects and / or provide a more effective treatment than current treatment options for IBD.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] 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 E, as well as other positions not expressly described herein.

[0026] 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-7C.B. Representative Embodiments of Sacral Neuromodulation Systems and Associated Stimulation Waveforms

[0027] 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). In other embodiments, the signal generator 1 10 can be positioned subcutaneously within or proximate the sacral pocket, the glute, the abdomen, the upper thigh, or another position relatively close to the sacral nerves. In other embodiments, such as described below with reference to Figure 3, the signal generator 110 can remain external to the patient during operation.

[0028] 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 depictsthe 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. In other embodiments, the signal delivery device 120 can be implanted proximate other target neural structures adjacent the sacral nerves, such as other sensory or motor neurons within the pelvic or upper thigh regions. Other target neural structures can include, for example, the femoral and / or obturator nerves. The signal delivery device 120 can carry features 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 E, 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.

[0029] 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.

[0030] 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, althoughin other embodiments some or all of the foregoing components can be stored in separate housings.

[0031] 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, switch between different stimulation waveforms, 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 1 10 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.

[0032] 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 detail throughout 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., bowel frequency, bowel urgency, diarrhea, rectal bleeding, abdominal pain, weight loss, etc.), and / or reduce inflammation causing the one or more symptoms of IBD. Indeed, in some embodiments, the electrical signal may be particularly effective at alleviating bowel urgency, which refers to the sudden and immediate need for a patient to have a bowel movement and is often identified bypatients as amongst the most debilitating symptoms of IBD. Additional details of electrical signals and stimulation regimes for treating IBD are described below with reference to Figures 2A and 2B.

[0033] 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.

[0034] In some embodiments, the system 100 can include multiple signal delivery devices 120 positioned proximate different target neural populations. For example, Figure 1 B illustrates an embodiment of the system 100 with multiple signal delivery devices for providing bilateral sacral stimulation and configured in accordance with some embodiments of the present technology. In particular, in addition to the signal delivery device 120 (“the first signal delivery device 120”), the system 100 further includes a second signal delivery device 130 in the embodiment depicted in Figure 1 B. The second signal delivery device 130 can be the same as or generally similar to the first signal delivery device 120. For example, the second signal delivery device 130 can include a lead or lead body 132 extending from the signal generator and carrying one or more electrodes or electrical contacts positionable proximate a target neural population. In the illustrated embodiments, for example, the first signal delivery device 120 extends through the S1 sacral foramen on a first side of the patient’s spinal midline, and the second signal delivery device 130 extends through the S1 sacral foramen on a second side of the patient’s spinal midline. Although shown as extending through sacral foramen at the same level, in other embodiments the first signal delivery device 120 can extend through a different level (e.g., the S3 sacral foramen) than the second signal delivery device 130.

[0035] The signal generator 110 can be programmed to transmit electrical signals to the first signal delivery device 120, the second signal delivery device 130, and / or both the first signal delivery device 120 and the second signal delivery device 130. For example, in some embodiments the signal generator 1 10 can simultaneously deliver an electrical signal to the first signal delivery device 120 and the second signal delivery device 130 to provide bilateral sacral stimulation to the patient (e.g., simultaneous bilateral stimulation). In other embodiments, the signal generator can alternate between delivering electrical signals to the first signal delivery device 120 and the second signal delivery device 130 (e.g., alternating bilateral stimulation). The electrical signal delivered to the first signal delivery device 120 can be the same as, or different than, the electrical signal delivered to the second signal delivery device 130.

[0036] Figure 1 C illustrates another embodiment of the system 100 with multiple signal delivery devices for stimulating different target structures and configured in accordance with some embodiments of the present technology. More specifically, in the illustrated embodiment, the system 100 includes the signal delivery device 120 (“the first signal delivery device 120”), the second signal delivery device 130, a third signal delivery device 140, and a fourth signal delivery device 150. Each of the signal delivery devices 120-150 can include a corresponding lead. For example, the first signal delivery device 120 includes the lead 122 as previously described, the second signal delivery device 130 includes the second lead 132, the third signal delivery device 140 includes a third lead 142, and the fourth signal delivery device 150 includes a fourth lead 152. Each of the leads 122-152 can extend from the signal generator 1 10 and include one or more electrodes or electrical contacts positionable proximate a target neural population. Each of the signal delivery devices 120-150 can be positioned proximate a different target neural population (e.g., to stimulate different sacral nerves or other neural structures proximate the sacral nerves, such as other sensory or motor neurons within the pelvic or upper thigh regions). Although illustrated as all being positioned on a same side of the patient (e.g., to provide unilateral stimulation), in some embodiments one or more of the signal delivery devices 120-150 extend across the patient’s midline (e.g., to provide bilateral stimulation). Moreover, although illustrated as having four signal delivery devices, in some embodiments the system 100 can include more or fewer signal delivery devices, such as one, two, three, five, six, seven, or eight.

[0037] As described above with reference to Figure 1 B, the signal generator 110 can be programmed to transmit electrical signals to each of the signal delivery devices 120-150. For example, in some embodiments the signal generator 110 can simultaneously deliver electrical signals to each of the signal delivery devices 120-150. In other embodiments, the signal generator can alternate between delivering electrical signals to individual ones of, or subsets of, the signal delivery devices 120-150. A user (e.g., healthcare provider) can program the signal generator 110 to deliver an electrical signal only to one, or only to a subset of, the signal delivery devices 120-150, e.g., based on a desired stimulation target. That is, a user can select which signal delivery devices 120-150 to activate based on which neural structure(s) are proximate the signal delivery devices 120-150. The electrical signals delivered to individual signal delivery devices can be the same as, or different than, electrical signals delivered to other individual signal delivery devices. For example, the electrical signal may be specific to the target neural structure associated with the corresponding signal delivery device.

[0038] In some embodiments, the patient P may receive multiple independent sacral stimulation systems. For example, Figure 1 D illustrates two sacral neuromodulation systems implanted in the patient P and configured to independently provide sacral stimulation in accordance with some embodiments of the present technology. More specifically, Figure 1 D illustrates the system 100 (“the first system 100”) as shown and described with reference to Figure 1 A implanted to stimulate a first side of the patient, and a second sacral neuromodulation system 160 (“the second system 160”) implanted to stimulate a second side of the patient across the spinal midline from the first side. Similar to the first system 100, the second system 160 can include an implantable signal generator 170 and one or more signal delivery devices 180. The signal generator 170 and the signal delivery device 180 can be the same as or generally similar to the signal generator 110 and the signal delivery device 120 described previously. The first system 100 and the second system 160 can be independently programmed and operated.

[0039] Figure 1 E 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 itcan 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.

[0040] Figure 1 E 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 target neural 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.

[0041] In some embodiments, test stimulation may be administered to a patient during a procedure to implant the signal delivery device 110. 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.

[0042] 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 1 10) described above with respect to Figures 1 A-1 E, 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.

[0043] 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 secondpulse 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.

[0044] 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.

[0045] 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 206 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.

[0046] 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 a pulse 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.

[0047] 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.

[0048] 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 about500 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.

[0049] 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.

[0050] 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, theamplitude (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 an amplitude that is at or above the sensory threshold, such that the patient can perceive the signal 200 being delivered. For example, the pulses 202 may have an amplitude that is between 100% of sensory threshold and 120% of sensory threshold, such as about 101 % of sensory threshold, 102% of sensory threshold, 103% of sensory threshold, 104% of sensory threshold, 105% of sensory threshold, etc. The sensory threshold can be determined by gradually increasing the amplitude of the signal 200 and having the patient report when they begin to feel a sensation (e.g., a tingling, pulsing, tapping, or paresthesia sensation). In some embodiments, the pulses 202 have an amplitude that is below the motor threshold of the patient. In such embodiments, the signal 200 itself 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. In other embodiments, the pulses 202 have an amplitude that is at or above the motor threshold.

[0051] 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 shown in Figure 2B can be generally similar to the signal 200 shown in Figure 2A, 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 differentamplitude 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).

[0052] 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. For example, the amplitude of the signal 250 can be gradually ramped upwardly at the onset of stimulation until a target (e.g., maximum) amplitude is reached. As a particular example, the amplitude could be gradually increased by a set amount (e.g., increased by 0.1 mA every pulse, every two pulses, every five pulses, etc.) and / or over a set period (e.g., increased for a duration of between about 1 second and about 30 seconds, or between about 2 seconds and about 20 seconds) until the target amplitude is reached. Without intending to be bound by theory, ramping the amplitude of the signal 250 at the onset of stimulation may reduce the likelihood of the stimulation jolting the patient at the onset of therapy, particularly in embodiments in which the target amplitude is set at or above the sensory threshold.

[0053] 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, and vice versa. Moreover, in some embodiments the pulse width, frequency, or other parameter is ramped instead of the amplitude.

[0054] 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. Forexample, the stimulation sessions may have a duration of between about 5 minutes and about 12 hours, such as between about 15 minutes and about 6 hours, or 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.

[0055] 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. Yet another expected advantage is that the off time between sequential sessions allows for neuroconsolidation of the signal. In some embodiments, however, electrical stimulation is applied for 24 hours per day.

[0056] The number and / or duration of stimulation sessions can be associated with various patient events or activities. In a first representative example, the stimulation sessions may occur while the patient is prandial. For example, the patient may receive one, two, three, or four 30-minute stimulation sessions per day, timed to occur while the patient is eating. In a second representative example, the electrical stimulation may be delivered during a single, one to six hour stimulation session per day, timed to (a) precede sleep (b) occur during sleep, or (c) both (a) and (b). In a third representative example, the electrical stimulation may be delivered during one or two one-hour stimulation sessions per day, timed to occur before, during, and / or after bowelmovements. In yet another representative example, the electrical stimulation may be delivered during short (e.g., 5-minute) stimulation sessions that occur each hour the patient is awake and / or active. For any of the foregoing examples, the signals can be applied using any of the signal parameters described for the signal 200 with reference to Figure 2A and the signal 250 with reference to Figure 2B. The foregoing examples are also provided by way of example only — the stimulation sessions can be applied at other times throughout the day, tied to other patient events, and / or according to other intervals beyond those described above.

[0057] In some embodiments, the patient can control when they receive the stimulation session and / or the type of stimulation they receive. For example, the patient may have access to a patient controller that can control operation of the signal generator (e.g., the signal generator 1 10 shown in Figure 1A) to initiate a stimulation session. Providing the patient with control over the timing of the stimulation sessions may be beneficial because the patient can initiate stimulation during a convenient time and / or when the patient experiences IBD symptoms (or an increase in the severity of IBD symptoms). In a representative example, the patient may select to initiate the stimulation session during the day (e.g., as opposed to at night), while avoiding certain activities (e.g., driving, periods of concentration, etc.), and / or during or after periods or activities that may lead to an increase in symptoms (e.g., during or after consuming food). In other embodiments, a signal generator can be programmed to automatically administer the stimulation session during predetermined intervals. For example, the signal generator can be programmed to automatically deliver a stimulation session every day at 1 PM or another selected time. As another example, the signal generator can be programmed to automatically deliver a stimulation session timed with certain patient activities. For example, the signal generator can be programmed to automatically deliver a stimulation session at a time the patient typically eats a meal (e.g., 8AM, 12PM, and / or 6PM). Additionally or alternatively, the signal generator can be programmed to automatically deliver a stimulation session at a time that the patient’s symptoms are typically the worst, which can be determined using patient feedback such as questionnaires, symptoms logs, etc. As yet another example, the signal generator can be programmed to automatically deliver a stimulation session based on a time the patient takes other medication (e.g., concurrent with taking medication, a specified duration before taking medication, or a specified duration after taking medication).Programming the signal generator to automatically administer the stimulation session may be advantageous because it eliminates the possibility of a patient forgetting to initiate therapy, and therefore may provide a more consistent therapy.

[0058] 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 being administered. In some embodiments, the “on” time can be between about 1 second and about 10 minutes, or between about 10 seconds and about 60 seconds, and the “off” time can be between about 1 second and about 10 minutes, or between about 30 seconds and about 500 seconds. 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; 30 seconds on, 180 seconds off; 30 seconds on 300 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.

[0059] 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, theterm 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).

[0060] In some embodiments, two or more electrical signals (e.g., the signal 200 described with reference Figure 2A and / or the signal 250 described with reference to Figure 2B) can be delivered concurrently. For example, in some embodiments a first signal is delivered continuously or intermittently for 24 hours per day as a base signal, and a second signal is delivered during discrete stimulation sessions (e.g., any of the stimulation sessions described previously). The first signal and the second signal can have any of the signal parameters described for the signal 200 and the signal 250 with reference to Figures 2A and 2B. However, the first signal may have a first set of signal delivery parameters (e.g., frequency, pulse width, amplitude, duty cycle, etc.), and the second signal may have a second set of signal delivery parameters that at least partially differ from the first set of signal delivery parameters. As a first example, the first signal may have a frequency of about 1 Hz, and the second signal may have a frequency of about 5 Hz. As another example, the first signal may be applied at a duty cycle of about 1 %, and the second signal can be applied at a duty cycle of about 50%. The foregoing are provided by way of example only, and the first signal can differ from the second signal in other ways. In some embodiments, the second signal can be programmed to be automatically administered at various time intervals, e.g., to correspond to various patient events or activities as described previously. In other embodiments, the second signal can be an “on-demand” signal that the patient can initiate, e.g., in response to an increase in IBD symptoms.

[0061] In embodiments in which multiple electrical signals are delivered to the patient, the first signal and the second signal can be delivered in cycles. For example, the first signal can be administered for a first period of time (e.g., a first stimulation session), and the second signal can be administered for a second period of time (e.g., a second stimulation session) after the first period of time. In such embodiments, the first period of time may partially overlap with the second period of time, although in other embodiments the first period of time does not overlap with the second period of time. In some embodiments, the timing of the first signal and the second signal can be set based on patient patterns. For example, the patient may receive a first (e.g., stronger) signalduring one or more portions of the day during which the patient is typically active, a second (e.g., weaker) signal during one or more portions of the day during which the patient is typically less active, and no stimulation during one or more portions of the day the patient is typically asleep.

[0062] The first signal and the second signal can be generated by the same signal generator (e.g., the signal generator 1 10 described with reference to Figure 1 A) or by different signal generators (e.g., the first signal generator 1 10 and the second signal generator 160, respectively, as described with reference to Figure 1 D). Likewise, the first signal and the second signal can be administered via the same signal delivery device (e.g., the signal delivery device 120 described with reference to Figure 1 ), or via different signal delivery devices (e.g., the signal delivery device 120 and the signal delivery device 130 described with reference to Figure 1 B). In embodiments in which the first signal and the second signal are delivered via the same signal delivery device, the first signal and the second signal can be delivered by different electrodes of the same signal delivery device (e.g., to enable concurrent delivery of the first signal and the second signal, if desired). In embodiments in which delivery of the first signal and the second signal do not temporally overlap, the first signal and the second signal may be delivered by the same combination of electrodes.

[0063] Although the foregoing describes using an implanted system to electrically stimulate the patient's sacral region to treat IBD, in other embodiments a transdermal sacral neuromodulation system can be used to electrically stimulate the patient’s sacral region to treat IBD. For example, Figure 3 illustrates another sacral neuromodulation system 300 (“the system 300”) for stimulating a patient’s sacral nerves and configured in accordance with some embodiments of the present technology. The system 300 can include a signal generator 310 and a signal delivery device 320. Similar to the system 100 described with reference to Figures 1 A and 1 E, the signal generator 310 can generate and transmit electrical signals to the signal delivery device 320, which can deliver the electrical signals to patient tissue. However, unlike the system 100 described with reference to Figures 1 A and 1 E, the signal generator 310 and signal delivery device 320 remain external to the patient. That is, neither the signal generator 310 nor the signal delivery device 320 are implanted in the patient. Electrical signals are instead transmitted through the patient’s skin and other tissue toward the target neural population (e.g., the sacral spinal nerves). In such embodiments, the signal parameterscan be adjusted such that the effective therapy provided at the target neural population is equivalent to the therapy provided in the embodiments described above. This may include, e.g., increasing an amplitude of the electrical signal to account for signal dissipation, providing a carrier signal to promote delivery of the therapy signal to the target neural population, etc. In some embodiments, the signal delivery device 320 can include a patch electrode or other energy delivery interface for delivering transdermal stimulation to the patient. In other embodiments, the signal delivery device 320 includes one or more coils for transmitting electromagnetic signals into the patient. The system 300 can therefore be configured to provide Transcutaneous Electrical Nerve Stimulation (“TENS”), Transcutaneous Magnetic Stimulation, or other transdermal stimulation therapies.

[0064] In some embodiments, a stimulation system may include some implanted components and some external components. For example, a stimulation system may include an external signal generator and an implanted signal delivery device. In such embodiments, the external signal generator can transmit electrical signals to the signal delivery via a wireless or wired connection device for delivery to a target neural population. In yet other embodiments, the sacral region can be stimulated using electroacupuncture or other techniques known for delivering electrical stimulation to patient tissue.

[0065] In some embodiments, the sacral neuromodulation described herein can be administered in combination with additional therapies for treating IBD. For example, the sacral neuromodulation described herein can be administered in addition to various pharmaceutical agents, such as biologies or small-molecule drugs for treating IBD. Indeed, without intending to be bound by theory, the sacral neuromodulation described herein may improve the effectiveness of these drugs.

[0066] As set forth above, drugs alone are often inadequate to control a patient’s IBD symptoms. Moreover, even in patients in which drugs are initially effective, the drugs often become less effective over time and / or begin to induce intolerable side effects. One potential mechanism underlying the loss of effectiveness and / or increase in side effects over time is the formation of antibodies to the drugs. Without intending to be bound by theory, delivering the sacral neuromodulation described herein may reduce the formation of these antibodies, e.g., by triggering the cholinergic anti-inflammatorypathway as described in greater detail below in Section D. Thus, in some embodiments, the sacral neuromodulation described herein can be delivered before, concurrent with, or after the delivery of IBD drugs. The potential advantage of this combinatorial therapy is twofold. First, the sacral neuromodulation may reduce or slow the formation of antibodies to the IBD drugs, which may prolong the efficacy of the IBD drugs and / or reduce side effects associated with the IBD drugs. Second, the sacral neuromodulation may itself treat, reduce, or ameliorate one or more symptoms of the patient’s IBD, such as bowel urgency, diarrhea, rectal bleeding, bowel frequency, sleep quality, fatigue, abdominal pain, and / or mucosal inflammation. Accordingly, in some embodiments the present technology includes concurrently administering sacral nerve stimulation and one or more pharmaceutical agents. In other embodiments, however, the sacral nerve stimulation described herein can be delivered without also delivering a pharmaceutical agent.

[0067] As also set forth above, the sacral neuromodulation described herein is expected to be useful in treating patients with IBD, including those with Crohn’s disease (“CD”) and ulcerative colitis (“UC”). This patient population includes both patients who have undergone a previous surgical intervention to address their CD or UC, and patients who have not. For example, some patients with severe CD or UC may undergo a partial or complete resection to remove some or all of their colons and / or other portions of their gut or digestive tract. Such patients may have additional surgery to create a pouch, sometimes referred to as an ileal pouch-anal anastomosis (IPAA) or J-pouch, while others have a permanent ostomy. The sacral neuromodulation described herein can be used to treat CD and UC patients regardless of whether they have had a previous surgical resection. Accordingly, as used herein, the terms “Crohn’s disease” and “ulcerative colitis” when identifying a patient condition to be treated can include patients with their digestive tract intact and patients who have had a previous surgical resection.C. Identifying Effective Stimulation Parameters and Schedules

[0068] In some embodiments, one or more combinations of signal delivery parameters and stimulation schedules can be tested to identify parameters and / or schedules that are effective for a particular patient. For example, Figure 4 is a flowchart of a method 400 of identifying an effective stimulation recipe for a particular patient in accordance with embodiments of the present technology. As used herein, the term“stimulation recipe” refers to a particular combination of signal delivery parameters (e.g., frequency, pulse width, amplitude, duty cycle, electrode combination, etc.) and stimulation schedules (e.g., number, duration, and / or timing of stimulation sessions).

[0069] The method 400 can begin at block 402 by delivering sacral nerve stimulation to a patient according to a particular (e.g., first) stimulation recipe. The stimulation recipe can include a first set of signal parameters (e.g., frequency, pulse width, amplitude, duty cycle, electrode combination, etc.), and a first particular stimulation schedule. The signal delivery parameters and stimulation schedule can be any of the parameters and schedules discussed throughout this Detailed Description. As a particular non-limiting example, the first set of signal delivery parameters can include a frequency of 5 Hz, a pulse width of 450 microseconds, and an amplitude set at or above the perception threshold. The first stimulation schedule can include providing one 1 -hour stimulation session per day (e.g., 1 hour on, 23 hours off).

[0070] The method 400 can continue at block 404 by determining whether the stimulation recipe is effective. This can include, for example, determining if the patient is responding to the particular stimulation recipe. In some embodiments, determining whether a patient is “responding” to the stimulation recipe includes determining whether the patient meets one or more predetermined thresholds associated with the therapy. Example thresholds include specific reductions in or improvements of one or more patient-reported symptoms or other metrics (e.g., numerical rating scales), such as bowel urgency, bowel frequency, Gl-pain, etc. Representative thresholds include, but are not limited to, at least 25% reduction, at least 50% reduction, or at least 75% reduction in the corresponding metric. In other embodiments, determining whether the patient is responding includes asking the patient if they are content with the therapy.

[0071] If at block 404 it is determined that the patient is responding to the particular stimulation recipe, then the method 400 can continue at block 406 by continuing to deliver SNS according to the particular stimulation recipe. The stimulation can be delivered according to the particular stimulation recipe on a more or less indefinite basis. Nevertheless, the patient can be periodically monitored to determine whether the effectiveness of the particular stimulation recipe decreases over time.

[0072] If at block 404 it is determined that the patient is not responding to the particular stimulation recipe, then the method 400 can continue at block 408 bychanging the stimulation recipe. This can include changing at least one signal delivery parameter and / or changing the stimulation schedule. As set forth above, signal delivery parameters that can be changed include frequency, pulse width, amplitude, duty cycle, and / or electrode combination. Changing the stimulation schedule can include changing the number of stimulation sessions, changing the duration of the stimulation sessions, and / or changing a timing of the stimulation sessions.

[0073] In some embodiments, changing the signal delivery parameter and / or stimulation schedule at block 408 includes increasing the effective dose of stimulation provided. This may include (a) increasing a frequency, pulse width, or amplitude of the signal, and / or (b) increasing the total duration that the stimulation is being actively delivered, e.g., by increasing the number or duration of stimulation sessions. Continuing with the non-limiting example from above, the stimulation schedule can change from one, 1 -hour stimulation session per day to four, 1 -hour stimulation sessions per day (e.g., 1 hour on, 5 hours off). This can be done with or without changing the signal delivery parameters. For example, the frequency, pulse width, amplitude, duty cycle, and / or electrode combination may remain unchanged relative to the stimulation provided at block 402. In some embodiments, the amplitude may be decreased in combination with increasing the total duration that the stimulation is being actively delivered.

[0074] The method 400 can continue at block 410 by delivering the SNS according to the new stimulation recipe to the patient, and then returning to the operation at block 404 to determine whether the new stimulation recipe is effective. If the new stimulation recipe is effective, the method 400 can proceed to the operation at block 406, described above. If the stimulation recipe is not effective, the method 400 can continue to the operation at block 408, also described above. The operations at block 404, 408, and 410 can be repeated two, three, four, five, or more times. In some embodiments, these operations are repeated until an effective stimulation recipe is identified. In other embodiments, these operations are repeated until a set number of predefined stimulation recipes has been tested.

[0075] For example, continuing with the non-limiting example from above, if the second stimulation recipe of four, 1 -hour stimulation sessions per day is not effective, then a third stimulation recipe could be tested. The third stimulation recipe could includedelivering the signal intermittently (e.g., 30 seconds on; 300 seconds off) 24 hours per day. If the third stimulation recipe is not effective, then a fourth stimulation recipe could be tested. The fourth stimulation recipe could include increasing the frequency to MHz and delivering continuous stimulation 24 hours per day. The foregoing recipes are provided by way of example only — one skilled in the art will appreciate that the stimulation recipes can include any combination of parameters and schedules described throughout this Detailed Description.

[0076] In some embodiments, the amplitude of the signal is changed in addition to changing the stimulation schedule. For example, stimulation delivered during discrete stimulation sessions (e.g., the first and second stimulation recipes explained above) may generally have a higher amplitude than stimulation delivered more frequently (e.g., the third and fourth stimulation recipes explained above). Without intending to be bound by theory, this may be because a patient may require a greater intensity of stimulation if they receive the stimulation less frequently. Therefore, in some embodiments stimulation recipes with relatively infrequent administration (e.g., 1 -4 sessions per day) may be suprathreshold or otherwise have a relatively higher amplitude, while stimulation recipes with more frequent administration (e.g., intermittent or continues stimulation for 24-hours per day) may be subthreshold or have a relatively lower amplitude. In other embodiments, the amplitude remains the same or about the same even as the stimulation schedule is changed.

[0077] In some embodiments, a treatment database can be generated and / or updated to assist with identifying particular stimulation recipes that may be effective for a particular patient. The database can store reference patient data, including patient demographics (e.g., age, sex, height, weight, body-mass index, etc.), patient diagnosis (e.g., Crohn’s disease, ulcerative colitis, etc.), previous interventions (e.g., drug therapy, surgical interventions such as partial or full colon / digestive tract resection, etc.) and patient symptoms (e.g., bowel urgency, bowel frequency, diarrhea, rectal bleeding, abdominal pain, fatigue, etc.). The reference patient data can also include treatment data, such as stimulation settings used by the particular patient, changes in stimulation settings by the patient, the effectiveness of the stimulation settings for the particular patient, and the like. The database can therefore identify and store correlations or associations between patient demographics, symptoms, and effective treatment parameters, which in turn can be used to identify a stimulation recipe likely to beeffective for a new patient. Correlations can be identified by receiving and / or generating scores or values associated with the patient data (e.g., scores based upon improvement in patient symptoms on a particular stimulation recipe, etc.) and aggregating, filtering, or otherwise analyzing the scores to identify statistically significant correlations.

[0078] For example, the database may identify that patients within a first subgroup (e.g., patients with ulcerative colitis that report bowel urgency as a predominate symptom) respond best to a first stimulation recipe, while patients within a second subgroup (e.g., patients with Crohn’s disease reporting bowel frequency and Gl-distress as the most troublesome symptoms) respond best to a second stimulation recipe that is different than the first recipe (and can include any of the stimulation recipes described throughout this Detailed Description). As a non-limiting example, the database may identify that patients with ulcerative colitis generally respond best to a first stimulation recipe that involves administering stimulation during four, 1 -hour sessions per day, and that patients with Crohn’s disease generally respond best to a second stimulation recipe that involves administering stimulation intermittently for 30 seconds on and 300 seconds off for 24-hours per day. If a new patient falls within the first subgroup, the treatment database can be referenced to determine that the patient should begin with the first stimulation recipe (e.g., four, 1 -hour sessions per day). If a new patient falls within the second subgroup, the treatment database can be referenced to determine that the patient should begin with the second stimulation recipe (e.g., 30 seconds on; 300 seconds off). In this way, the time to identify an effective stimulation recipe for a given patient may be reduced.

[0079] Moreover, the database can also be used to identify stimulation recipes that are unlikely to be effective for a given patient. For example, the database may identify that patients within the first subgroup are unlikely to respond to a third stimulation recipe. This correlation can either be dependent on or independent of whether the patient responds to the first stimulation recipe. Thus, if the patient does not respond to the first stimulation recipe, the database can instruct a user to avoid the third stimulation recipe since it too is unlikely to be effective for the particular patient. In this way, the database may reduce testing of stimulation recipes that are unlikely to be effective.

[0080] In some embodiments, the database can identify and generate recommended stimulation recipes using one or more algorithms or statisticaltechniques. For example, the database can incorporate one or more statistical techniques such as clustering or regression analysis / models to match a particular patient with one or more reference patients stored in the database, e.g., to identify a particular stimulation recipe likely to be effective for the particular patient based on the experience of similarly situated reference patients. Alternatively or additionally, the database can incorporate one or more Artificial Intelligence (“Al”) platforms, models, or techniques such as neural networks, machine learning models, or the like, to identify reference patients and optimize recommendations for the particular patient based on a comparison of the particular patient to the reference patient and the experience of the reference patient. The Al models can be trained based on validated reference patient data sets. In some embodiments, the database can identify particular patient data needed to or helpful for matching the particular patient with one or more reference patients and / or generating a therapy recommendation. The database can then generate one or more questions for the particular patient for collecting the particular patient data.

[0081] Regardless of the model used to generate the recommendations, the database can be periodically or continuously updated with new reference patient data. For example, patients can self-report the stimulation recipes and effectiveness (e.g., via a website, secure portal, mobile phone application, or the like). The new reference patient data can be verified and automatically incorporated into the statistical or Al model used to identify correlations and provide therapy recommendations. In this way, the database can be adaptive and optimized over time as more reference patient data is received, which in turn may reduce the time and number of stimulation recipes that must be tested before finding an effective stimulation recipe for any particular patient. In some embodiments, the Al can be configured to use a federated learning structure by processing the data at the source of the implanted device or accompanying external controllers to ensure that the data remains decentralized and private.

[0082] The database can be stored on or distributed across a remote or local computing system, including a server, a computing device, and / or the cloud. The database can be accessed by a physician or other healthcare provider, e.g., to determine which stimulation recipes to test on a particular patient. In some embodiments, the database is a central database that can be accessed by a plurality of physicians or healthcare providers, and can enable a physician to share stimulationrecipes that were effective for their patients. In some embodiments, the database can also be accessed by a patient.D. Representative Mechanisms of Action

[0083] The autonomic nervous system regulates many bodily functions, such as heart rate, digestion, respiratory rate, etc. The autonomic nervous system also has a fundamental role in mediating inflammation. For example, the autonomic nervous system can control release of various immunomodulatory substances (e.g., pro- inflammatory cytokines, anti-inflammatory cytokines, etc.) to mediate inflammation. This is largely controlled by the sympathetic nervous system and the parasympathetic nervous system. When activated, the sympathetic nervous system may induce release of pro-inflammatory substances (e.g., pro-inflammatory cytokines such as TNF-o, IL-1 , IL-18, etc.), whereas the parasympathetic nervous system may induce release of antiinflammatory substances (e.g., anti-inflammatory cytokines such as IL-4, IL-10, etc.). Normally, the sympathetic and parasympathetic systems work in sync to promote immune responses and modulate healing. However, in certain patients, the sympathetic and parasympathetic systems may be imbalanced or dysfunctional, which may lead to chronic inflammation. Such patients may have a chronic imbalance between serum levels of pro-inflammatory cytokines and anti-inflammatory cytokines. An example of a chronic condition in which patients may have an imbalance between pro-inflammatory cytokines and anti-inflammatory cytokines includes IBD.

[0084] The cholinergic anti-inflammatory pathway (CAP) is a neural mechanism that inhibits pro-inflammatory cytokine release. For example, when activated, the CAP inhibits synthesis of certain pro-inflammatory molecules (e.g., TNF) in the liver and spleen and reduces the amount of circulating pro-inflammatory molecules. CAP receives inputs from multiple peripheral nerves, including the vagus nerve, the splenic nerve, and the sacral nerve. It has been previously demonstrated that stimulating the vagus nerve activates the CAP, which in turn has been shown to decrease pro- inflammatory cytokine production / release and reduce inflammation.

[0085] Without being bound by theory, one potential mechanism of action underlying the treatment of IBD with sacral nerve stimulation includes activating the CAP. In some embodiments, this may occur via activation of afferent nerve fibers, which can transmit signals from the sacral nerve toward the brain, which in turn may activatethe CAP. In other embodiments, this may occur via direct activation of the CAP, without involvement of the central nervous system. Regardless, activating the CAP may cause T cells within the spleen to release the neurotransmitter acetylcholine, which may bind to a7 nicotinic acetylcholine receptors on macrophages in the spleen. This may reduce the ability to release inflammatory cytokines, including, for example, TNF-a, IL-6, and / or IL-1 p. Activating the CAP may also cause direct release of acetylcholine from one or more local nerves (e.g., the splenic nerve, the sacral nerve), bypassing the need for the T-cell intermediary. The reduction in pro-inflammatory cytokines may help restore the balance between pro-inflammatory cytokines and anti-inflammatory cytokines. This in turn may normalize the balance between the sympathetic and parasympathetic nervous systems, leading to reduced inflammation and improvement in IBD-related symptoms.

[0086] Another potential mechanism of action involves activation of efferent nerve fibers that extend from the sacral nerves toward the gastrointestinal tract (e.g., the colon). For example, activating efferent nerve fibers that innervate the distal bowel may promote the release of acetylcholine from myenteric neurons. The secreted acetylcholine can then bind to receptors (e.g., a7 nicotinic acetylcholine receptors) on macrophages proximate the gastrointestinal tract. The binding of acetylcholine to a7 receptors on the macrophages can reduce the release of pro-inflammatory cytokines and / or block pro-inflammatory cytokines, as described above. The reduction in pro- inflammatory cytokines may reduce inflammation of the gastrointestinal tract, leading to an improvement in IBD-related symptoms.

[0087] The foregoing mechanisms of action are provided as potential explanations underlying the efficacy observed in treating IBD using sacral nerve stimulation. However, the benefit of sacral nerve stimulation in patients with IBD may arise through alternative mechanisms, in addition to or in lieu of the mechanism described herein. For example, although the foregoing mechanisms largely involve reducing and / or blocking pro-inflammatory cytokines, other mechanisms may include increasing and / or promoting anti-inflammatory cytokines. Accordingly, the present technology is not limited to a particular mechanism of action, unless expressly stated otherwise.E. Animal & Clinical Data

[0088] Boomerang Medical, Inc., the assignee of the present application, performed an animal study showing the benefit of sacral nerve stimulation on a ratmodel of IBD. To conduct the study, nine Sprague-Dawley rats were anesthetized and received surgically implanted electrodes electrically connected to the third sacral nerve. During a first post-implant period beginning 8 days following electrode implantation, the rats were administered 4% Dextran Sulfate Salt (DSS) daily to induce gastrointestinal inflammation (e.g., as a model of ulcerative colitis). The rats were then divided into a first group (“the test group”) that received sacral nerve stimulation during a second postimplant period, and a second group (“the control group”) that did not receive stimulation during the second post-implant period. For the test group, stimulation was applied at a frequency of 5.2 Hz, a pulse width of 210 microseconds, and at a voltage amplitude of 80-90% of motor threshold. Stimulation was applied once daily for one hour. During the one-hour stimulation session, stimulation was applied continuously. Both groups of rats were scored daily on the Disease Activity Index (DAI) during the first post-implant period and the second post-implant period. The DAI included ranking weight loss, stool consistency, and bleeding on a four-point scale (0, 1 , 2, 3), with higher numbers for each category reflecting more severe scores. The score for each rat was then summed to determine the rat’s daily summed DAI score (with a maximum daily score of 9).

[0089] Figure 5A is a graph 500 comparing the average daily DAI summed score for the test group that received daily stimulation during the second post-implant period (line 510) and the control group that did not receive daily stimulating during the second post-implant period (line 520). More specifically, the x-axis measures the number of days post-implant, and the y-axis measures the average summed DAI score. As shown, DAI scores for the test group and the control group increased during the first postimplant period (labeled on the graph 500 as “DSS”) as a result of being administered DSS. After the first post-implant period (beginning at day 14), the rats no longer received DSS and instead either received stimulation (the test group) or sham stimulation (the control group) during the second post-implant period (labeled on the graph 500 as “SNS”). As shown, DAI scores decreased for both the test group and the control group during the second post-implant stimulation period. However, the DAI scores for the test group decreased at a faster rate than DAI scores for the control group, indicating that rats receiving the stimulation recovered faster from the DSS induced inflammation.

[0090] Figure 5B is a graph 550 showing the “area under the curve” (“AUC”) for line 510 and line 520 from Figure 5A during both the first stimulation period corresponding to the period labeled as “DSS” in Figure 5A and the second stimulationperiod corresponding to the period labeled as “SNS” in Figure 5A. A greater AUC indicates a higher average DAI during the relevant period, whereas a lower AUC indicates a lower average DAI during the relative period. As shown, during the first stimulation period during which the rats were being administered DSS but not receiving any stimulation, the AUC for the test group (identified by reference number 560) and the AUC for the control group (identified by reference number 570) were generally the same. However, during the second stimulation period during which the test group received sacral nerve stimulation and the control group did not, the AUC for the test group (identified by reference number 565) was notably lower than the AUC for the control group (identified by reference number 575). This further validates that the test group demonstrated a faster reduction in AUC than the control group, reflecting that the sacral nerve stimulation helped lower DAI scores in a rat model of IBD. Without intending to be bound by theory, the animal data reported in Figures 5A and 5B therefore supports that sacral nerve stimulation may be beneficial in treating inflammatory diseases such as IBD.

[0091] Boomerang Medical, Inc. has also performed human clinical trials that show the benefit of using sacral nerve stimulation to treat IBD. 30 total patients were enrolled in a pilot study, including 18 patients diagnosed with ulcerative colitis (“UC”) and 12 patients diagnosed with Crohn’s disease (“CD”). All patients began by receiving sacral nerve stimulation for a single 1 -hour stimulation session per day (e.g., 1 hour on, 23 hours off). The stimulation had a frequency of 5 Hz, a pulse width of 450 microseconds, and an amplitude set initially around the sensation threshold or just below the sensation threshold. If a patient was not responding to the stimulation, the patient was escalated to receiving four 1 -hour stimulation sessions per day (e.g., 1 hour on; 5 hours off).

[0092] Figure 6A is a graph 600 illustrating the average Mayo Score for the 18 UC patients at baseline, 3 months after initiation of therapy, and 6 months after initiation of therapy. Similar to the DAI described above, the average Mayo Score for UC includes sub scores of stool frequency, rectal bleeding, and endoscopic appearance on a four- point scale (0, 1 , 2, 3), with higher numbers for each category reflecting more severe scores. As shown in the graph 600, at baseline the UC patients had an average Mayo Score of about 4.1 . After receiving stimulation for 3 months, the average May Score for these patients dropped by 46%, to about 2.2. This benefit was maintained at 6 months.Accordingly, Figure 6A illustrates that the sacral nerve stimulation described herein is effective at reducing the severity of UC.

[0093] Figure 6B is a graph 650 illustrating the average Crohn’s Disease Activity Index (CDAI) for the 12 CD patients at baseline, 4 weeks after initiation of therapy, 3 months after initiation of therapy, and 6 months after initiation of therapy. Similar to the Mayo Score for UC, the CDAI is a numerical rating that assesses the severity of a patient’s CD by summing and weighting various categories (e.g., abdominal pain, stool softness, etc.). The CDAI score can range from 0 (normal) to around 600 (very severe disease). As shown in the graph 650, at baseline the CD patients had median CDAI score of nearly 250. After receiving stimulation for 4 weeks, the median CDAI score dropped by 31 %, to about 170. This benefit was largely maintained at 3 months (-28% relative to baseline), and further improved at 6 months (47% relative to baseline, or about 130). Accordingly, Figure 6B illustrates that the sacral nerve stimulation described herein is effective at reducing the severity of CD.

[0094] During the pilot study, certain individual symptoms were also monitored and scored. For example, for both the UC and CD cohorts, bowel urgency was scored and tracked using a 7-point numerical rating score, with 0 representing no bowel urgency and 7 representing the worst possible bowel urgency. Figure 7A is a graph 700 showing the average bowel urgency scores for both the UC and CD cohorts combined at baseline and at various intervals after therapy initiation, Figure 7B is a graph 710 showing the average bowel urgency scores for the UC cohort at baseline and at various intervals after therapy initiation, and Figure 7C is a graph 720 showing the average bowel urgency scores for the CD cohort at baseline and at various intervals after therapy initiation. Referring collectively to Figures 7A-7C, both UC and CD patients had improved (i.e., reduced) bowel urgency scores while receiving the sacral nerve stimulation. However, UC patients demonstrated a greater reduction (48% reduction at 3 months, 52% reduction at 6 months) than CD patients (25% at 3 months). Thus, in some embodiments the stimulation therapy described herein may be particularly effective at treating bowel urgency in patients with UC.F. Representative Examples

[0095] 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 presenttechnology. 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 treating a patient with Inflammatory Bowel Disease (IBD), the method comprising: delivering electrical stimulation to a sacral nerve of the patient in accordance with a first stimulation recipe, wherein the first stimulation recipe includes (a) a first set of stimulation parameters including a frequency within a frequency range of from about 1 Hz to about 10 Hz and a pulse width within a pulse width range of from about 50 microseconds to about 700 microseconds, and (b) a first stimulation schedule comprising a single stimulation session per day of between about 30 minutes and about 3 hours; determining whether the electrical stimulation is effective at treating the patient’s IBD; and in response to determining that the electrical stimulation is not effective, delivering electrical stimulation to the sacral nerve of the patient in accordance with a second stimulation recipe different than the first stimulation recipe, wherein the second stimulation recipe provides an increased dose of stimulation to the patient relative to the first recipe, and wherein the increased dose is provided by at least one of increasing the duration of the stimulation session and / or increasing the number of stimulation sessions per day.2. The method of example 1 wherein the patient has bowel urgency associated with the IBD, and wherein determining whether the electrical stimulation is effective at treating the patient’s IBD includes determining whether the electrical stimulation is effective at treating the patient’s bowel urgency.3. The method of example 1 or example 2 further comprising using a treatment database to identify the first stimulation recipe, wherein the treatment database stores reference patient data for a plurality of reference patients, the reference patient data including patient demographic data and patient treatment data.4. The method of example 3 wherein the treatment database stores correlations between patient symptoms and effective stimulation recipes.5. The method of any of examples 1 -4 wherein the increased dose is provided by delivering stimulation sessions per day of between about 30 minutes and about 3 hours each.6. The method of any of examples 1 -4 wherein the increased dose is provided by increasing the duration of the stimulation session.7. The method of any of examples 1 -6 wherein the first set of stimulation parameters remains the same for both the first stimulation recipe and the second stimulation recipe.8. The method of any of examples 1 -6 wherein the second stimulation recipe includes a second set of stimulation parameters, and wherein at least one parameter of the second set of stimulation parameters differs from the corresponding parameter of the first set of stimulation parameters.9. The method of example 8 wherein the at least one parameter includes at least one of the frequency or the pulse width.10. The method of any of examples 1 -9 wherein the frequency range is from about 4 Hz to about 6 Hz.1 1. The method of any of examples 1 -10 wherein the pulse width range is from about 400 microseconds to about 600 microseconds.12. The method of any of examples 1 -11 wherein determining whether the electrical stimulation is effective includes receiving a patient input indicating whether the electrical stimulation is effective.13. The method of any of examples 1 -11 wherein determining whether the electrical stimulation is effective includes: receiving one or more metrics representative of the effectiveness of the electrical stimulation; and comparing the one or more metrics to one or more corresponding predetermined thresholds, wherein the electrical stimulation is determined to be ineffective if the one or more metrics fail to meet the one or more corresponding predetermined thresholds.14. The method of example 13 wherein the one or more metrics include metrics associated with bowel urgency.15. The method of example 13 wherein the one or more metrics include metrics associated with Gl-pain.16. A method of treating a patient with Inflammatory Bowel Disease (IBD), the method comprising: programming a sacral nerve stimulation system to deliver electrical stimulation to a sacral nerve of the patient in accordance with a first stimulation recipe, wherein the first stimulation recipe includes (a) a first set of stimulation parameters including a frequency within a frequency range of from about 1 Hz to about 10 Hz and a pulse width within a pulse width range of from about 50 microseconds to about 700 microseconds, and (b) a first stimulation schedule comprising a single stimulation session per day of between about 30 minutes and about 3 hours; and at least partially in response to an indication that the electrical stimulation is not effective at treating the patient’s IBD, programming the sacral nerve stimulation system to deliver the electrical stimulation to the sacral nerveof the patient in accordance with a second stimulation recipe different than the first stimulation recipe, wherein the second stimulation recipe provides an increased dose of stimulation to the patient relative to the first recipe, and wherein the increased dose is provided by at least one of increasing the duration of the stimulation session and / or increasing the number of stimulation sessions per day.17. The method of example 16 wherein the patient has bowel urgency associated with the patient’s IBD, and wherein programming the sacral nerve stimulation system to deliver the electrical stimulation in accordance with the second stimulation recipe is performed in response to the indication indicating the electrical stimulation is not effective at treating the bowel urgency.18. The method of example 16 or example 17 wherein the sacral nerve stimulation system includes an implantable signal generator, and wherein programming the sacral nerve stimulation system includes programming the implantable signal generator to generate the electrical stimulation.19. The method of any of examples 16-18 wherein the increased dose of the second stimulation recipe is provided by increasing the duration of the stimulation sessions relative to the first stimulation recipe.20. The method of any of examples 16-18 wherein the increased dose of the second stimulation recipe is provided by increasing the number of stimulation sessions administered per day relative to the first stimulation recipe.21 . The method of any of examples 16-18 wherein the increased dose of the second stimulation recipe is provided by both increasing the duration of the stimulation sessions and increasing the number of stimulation sessions administered per day, relative to the first stimulation recipe.22. The method of any of examples 16-20 wherein the first set of stimulation parameters remains the same for both the first stimulation recipe and the second stimulation recipe.23. The method of any of examples 16-20 wherein the second stimulation recipe includes a second set of stimulation parameters, and wherein at least one parameter of the second set of stimulation parameters differs from the corresponding parameter of the first set of stimulation parameters.24. The method of any of examples 16-23 wherein: the frequency range is from about 4 Hz to about 6 Hz, the pulse width range is from about 400 microseconds to about 600 microseconds, and the first set of stimulation parameters further includes a signal amplitude at or above a sensation threshold of the patient.25. A method of treating bowel urgency in a patient diagnosed with Inflammatory Bowel Disease (IBD), the method comprising: delivering electrical stimulation to a sacral nerve of the patient in accordance with a first stimulation recipe, wherein the first stimulation recipe includes (a) a first set of stimulation parameters including a frequency within a frequency range of from about 4 Hz to about 6 Hz and a pulse width within a pulse width range of from about 400 microseconds to about 600 microseconds, and (b) a first stimulation schedule comprising a single stimulation session per day of between about 30 minutes and about 3 hours; receiving a metric representative of the effectiveness of the electrical stimulation at addressing the bowel urgency; comparing the metric to a corresponding predetermined threshold; and at least partially in response to the metric failing to meet to the predetermined threshold, delivering electrical stimulation to the sacral nerve of the patient in accordance with a second stimulation recipe different than the first stimulation recipe, wherein the second stimulation recipe provides an increased dose of stimulation to the patient relative to the first recipe, andwherein the increased dose is provided by at least one of increasing the duration of the stimulation session and / or increasing the number of stimulation sessions per day.26. The method of example 25 wherein the increased dose of the second stimulation recipe is provided by increasing the duration of the stimulation sessions relative to the first stimulation recipe.27. The method of example 25 wherein the increased dose of the second stimulation recipe is provided by increasing the number of stimulation sessions administered per day relative to the first stimulation recipe.28. The method of any of examples 25-27 wherein the first set of stimulation parameters remains the same for both the first stimulation recipe and the second stimulation recipe.29. The method of any of examples 25-27 wherein the second stimulation recipe includes a second set of stimulation parameters, and wherein at least one parameter of the second set of stimulation parameters differs from the corresponding parameter of the first set of stimulation parameters.30. A method of treating bowel urgency in a patient with Inflammatory Bowel Disease (IBD), the method comprising: generating an electrical signal having a frequency within a frequency range of from about 4 Hz to about 6 Hz, a pulse width in a pulse width range of from about 400 microseconds to about 600 microseconds, and an amplitude at or above a sensation threshold of the patient; and delivering the electrical signal to a sacral nerve of the patient via an implanted signal delivery device positioned adjacent the sacral nerve, wherein the electrical signal reduces bowel urgency in the patient.31 . The method of example 30 wherein the frequency is about 5 Hz.32. The method of example 30 or example 31 wherein the pulse width is about 450 microseconds.33. The method of any of examples 30-32 wherein the patient has ulcerative colitis.34. The method of any of examples 30-33 wherein the electrical signal reduces bowel urgency in the patient by at least 25% relative to a baseline level of bowel urgency prior to the patient receiving the electrical signal.35. The method of any of examples 30-33 wherein the electrical signal reduces bowel urgency in the patient by at least 50% relative to a baseline level of bowel urgency prior to the patient receiving the electrical signal.36. The method of any of examples 30-35 wherein the generating and delivering operations are performed in response to the patient having bowel urgency associated with IBD.37. The method of any of examples 30-35 wherein the electrical signal is delivered in discrete stimulation sessions each having a duration of between about 30 minutes and about 3 hours.38. The method of example 37 wherein the electrical signal is delivered during a single stimulation session per day.39. The method of example 37 wherein the electrical signal is delivered during two or more stimulation sessions per day.40. A method of treating bowel urgency in a patient with Inflammatory Bowel Disease (IBD), the method comprising: programming a signal generator to generate and deliver an electrical signal to a sacral nerve of the patient via an implanted signal delivery device positioned adjacent the sacral nerve,wherein the electrical signal has a frequency within a frequency range of from about 4 Hz to about 6 Hz, a pulse width in a pulse width range of from about 400 microseconds to about 600 microseconds, and an amplitude at or above a sensation threshold of the patient, and wherein the electrical signal reduces bowel urgency in the patient.41 . The method of example 40 wherein the frequency is about 5 Hz.42. The method of example 40 or example 41 wherein the pulse width is about 450 microseconds.43. The method of any of examples 40-42 wherein the patient has ulcerative colitis.44. The method of any of examples 40-43 wherein the electrical signal reduces bowel urgency in the patient by at least 25% relative to a baseline level of bowel urgency prior to the patient receiving the electrical signal.45. The method of any of examples 40-43 wherein the electrical signal reduces bowel urgency in the patient by at least 50% relative to a baseline level of bowel urgency prior to the patient receiving the electrical signal.46. The method of any of examples 40-45 wherein the programming operation is performed at least partially in response to the patient having bowel urgency associated with IBD.47. The method of any of examples 40-46 wherein the electrical signal is delivered in discrete stimulation sessions each having a duration of between about 30 minutes and about 3 hours.48. The method of example 47 wherein the electrical signal is delivered during a single stimulation session per day.49. The method of example 47 wherein the electrical signal is delivered during two or more stimulation sessions per day.50. A sacral nerve stimulation system for treating bowel urgency in a patient with Inflammatory Bowel Disease (IBD), the system comprising: an implantable signal delivery element positionable proximate a sacral nerve of the patient; and a signal generator programmed with instructions that, when executed, cause the signal generator to generate and deliver an electrical signal to the sacral nerve of the patient via the implantable signal delivery element, wherein the electrical signal has a frequency within a frequency range of from about 4 Hz to about 6 Hz, a pulse width in a pulse width range of from about 400 microseconds to about 600 microseconds, and an amplitude at or above a sensation threshold of the patient, and wherein the electrical signal reduces bowel urgency in the patient.51 . The system of example 50 wherein the frequency is about 5 Hz.52. The system of example 50 or example 51 wherein the pulse width is about 450 microseconds.53. The system of any of examples 50-52 wherein the signal generator is implantable.54. The system of any of examples 50-52 wherein the signal generator is an external signal generator.55. The system of any of examples 50-54 wherein the electrical signal is delivered in discrete stimulation sessions each having a duration of between about 30 minutes and about 3 hours.56. The system of example 55 wherein the electrical signal is delivered during a single stimulation session per day.57. The system of example 55 wherein the electrical signal is delivered during two or more stimulation sessions per day.G. Conclusion

[0096] 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.

[0097] 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.

[0098] 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 statedrange 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 may independently 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

1. CLAIMSI / We claim:1 . A method of treating a patient with Inflammatory Bowel Disease ( I BD), the method comprising: delivering electrical stimulation to a sacral nerve of the patient in accordance with a first stimulation recipe, wherein the first stimulation recipe includes (a) a first set of stimulation parameters including a frequency within a frequency range of from about 1 Hz to about 10 Hz and a pulse width within a pulse width range of from about 50 microseconds to about 700 microseconds, and (b) a first stimulation schedule comprising a single stimulation session per day of between about 30 minutes and about 3 hours; determining whether the electrical stimulation is effective at treating the patient’s IBD; and in response to determining that the electrical stimulation is not effective, delivering electrical stimulation to the sacral nerve of the patient in accordance with a second stimulation recipe different than the first stimulation recipe, wherein the second stimulation recipe provides an increased dose of stimulation to the patient relative to the first recipe, and wherein the increased dose is provided by at least one of increasing the duration of the stimulation session and / or increasing the number of stimulation sessions per day.

2. The method of claim 1 wherein the patient has bowel urgency associated with the IBD, and wherein determining whether the electrical stimulation is effective at treating the patient’s IBD includes determining whether the electrical stimulation is effective at treating the patient’s bowel urgency.

3. The method of claim 1 further comprising using a treatment database to identify the first stimulation recipe, wherein the treatment database stores referencepatient data for a plurality of reference patients, the reference patient data including patient demographic data and patient treatment data.

4. The method of claim 3 wherein the treatment database stores correlations between patient symptoms and effective stimulation recipes.

5. The method of claim 1 wherein the increased dose is provided by delivering stimulation sessions per day of between about 30 minutes and about 3 hours each.

6. The method of claim 1 wherein the increased dose is provided by increasing the duration of the stimulation session.

7. The method of claim 1 wherein the first set of stimulation parameters remains the same for both the first stimulation recipe and the second stimulation recipe.

8. The method of claim 1 wherein the second stimulation recipe includes a second set of stimulation parameters, and wherein at least one parameter of the second set of stimulation parameters differs from the corresponding parameter of the first set of stimulation parameters.

9. The method of claim 8 wherein the at least one parameter includes at least one of the frequency or the pulse width.

10. The method of claim 1 wherein the frequency range is from about 4 Hz to about 6 Hz.1 1 . The method of claim 1 wherein the pulse width range is from about 400 microseconds to about 600 microseconds.

12. The method of claim 1 wherein determining whether the electrical stimulation is effective includes receiving a patient input indicating whether the electrical stimulation is effective.

13. The method of claim 1 wherein determining whether the electrical stimulation is effective includes: receiving one or more metrics representative of the effectiveness of the electrical stimulation; and comparing the one or more metrics to one or more corresponding predetermined thresholds, wherein the electrical stimulation is determined to be ineffective if the one or more metrics fail to meet the one or more corresponding predetermined thresholds.

14. The method of claim 13 wherein the one or more metrics include metrics associated with bowel urgency.

15. The method of claim 13 wherein the one or more metrics include metrics associated with Gl-pain.

16. A method of treating a patient with Inflammatory Bowel Disease (IBD), the method comprising: programming a sacral nerve stimulation system to deliver electrical stimulation to a sacral nerve of the patient in accordance with a first stimulation recipe, wherein the first stimulation recipe includes (a) a first set of stimulation parameters including a frequency within a frequency range of from about 1 Hz to about 10 Hz and a pulse width within a pulse width range of from about 50 microseconds to about 700 microseconds, and (b) a first stimulation schedule comprising a single stimulation session per day of between about 30 minutes and about 3 hours; and at least partially in response to an indication that the electrical stimulation is not effective at treating the patient’s IBD, programming the sacral nerve stimulation system to deliver the electrical stimulation to the sacral nerve of the patient in accordance with a second stimulation recipe different than the first stimulation recipe, wherein the second stimulation recipe provides an increased dose of stimulation to the patient relative to the first recipe, and wherein the increased dose is provided by at least one of increasingthe duration of the stimulation session and / or increasing the number of stimulation sessions per day.

17. The method of claim 16 wherein the patient has bowel urgency associated with the patient’s I BD, and wherein programming the sacral nerve stimulation system to deliver the electrical stimulation in accordance with the second stimulation recipe is performed in response to the indication indicating the electrical stimulation is not effective at treating the bowel urgency.

18. The method of claim 16 wherein the sacral nerve stimulation system includes an implantable signal generator, and wherein programming the sacral nerve stimulation system includes programming the implantable signal generator to generate the electrical stimulation.

19. The method of claim 16 wherein the increased dose of the second stimulation recipe is provided by increasing the duration of the stimulation sessions relative to the first stimulation recipe.

20. The method of claim 16 wherein the increased dose of the second stimulation recipe is provided by increasing the number of stimulation sessions administered per day relative to the first stimulation recipe.

21. The method of claim 16 wherein the increased dose of the second stimulation recipe is provided by both increasing the duration of the stimulation sessions and increasing the number of stimulation sessions administered per day, relative to the first stimulation recipe.

22. The method of claim 16 wherein the first set of stimulation parameters remains the same for both the first stimulation recipe and the second stimulation recipe.

23. The method of claim 16 wherein the second stimulation recipe includes a second set of stimulation parameters, and wherein at least one parameter of the secondset of stimulation parameters differs from the corresponding parameter of the first set of stimulation parameters.

24. The method of claim 16 wherein: the frequency range is from about 4 Hz to about 6 Hz, the pulse width range is from about 400 microseconds to about 600 microseconds, and the first set of stimulation parameters further includes a signal amplitude at or above a sensation threshold of the patient.

25. A method of treating bowel urgency in a patient diagnosed with Inflammatory Bowel Disease (IBD), the method comprising: delivering electrical stimulation to a sacral nerve of the patient in accordance with a first stimulation recipe, wherein the first stimulation recipe includes (a) a first set of stimulation parameters including a frequency within a frequency range of from about 4 Hz to about 6 Hz and a pulse width within a pulse width range of from about 400 microseconds to about 600 microseconds, and (b) a first stimulation schedule comprising a single stimulation session per day of between about 30 minutes and about 3 hours; receiving a metric representative of the effectiveness of the electrical stimulation at addressing the bowel urgency; comparing the metric to a corresponding predetermined threshold; and at least partially in response to the metric failing to meet to the predetermined threshold, delivering electrical stimulation to the sacral nerve of the patient in accordance with a second stimulation recipe different than the first stimulation recipe, wherein the second stimulation recipe provides an increased dose of stimulation to the patient relative to the first recipe, and wherein the increased dose is provided by at least one of increasing the duration of the stimulation session and / or increasing the number of stimulation sessions per day.

26. The method of claim 25 wherein the increased dose of the second stimulation recipe is provided by increasing the duration of the stimulation sessions relative to the first stimulation recipe.

27. The method of claim 25 wherein the increased dose of the second stimulation recipe is provided by increasing the number of stimulation sessions administered per day relative to the first stimulation recipe.

28. The method of claim 25 wherein the first set of stimulation parameters remains the same for both the first stimulation recipe and the second stimulation recipe.

29. The method of claim 25 wherein the second stimulation recipe includes a second set of stimulation parameters, and wherein at least one parameter of the second set of stimulation parameters differs from the corresponding parameter of the first set of stimulation parameters.

30. A method of treating bowel urgency in a patient with Inflammatory Bowel Disease (IBD), the method comprising: generating an electrical signal having a frequency within a frequency range of from about 4 Hz to about 6 Hz, a pulse width in a pulse width range of from about 400 microseconds to about 600 microseconds, and an amplitude at or above a sensation threshold of the patient; and delivering the electrical signal to a sacral nerve of the patient via an implanted signal delivery device positioned adjacent the sacral nerve, wherein the electrical signal reduces bowel urgency in the patient.31 . The method of claim 30 wherein the frequency is about 5 Hz.

32. The method of claim 30 wherein the pulse width is about 450 microseconds.

33. The method of claim 30 wherein the patient has ulcerative colitis.-SO-34. The method of claim 30 wherein the electrical signal reduces bowel urgency in the patient by at least 25% relative to a baseline level of bowel urgency prior to the patient receiving the electrical signal.

35. The method of claim 30 wherein the electrical signal reduces bowel urgency in the patient by at least 50% relative to a baseline level of bowel urgency prior to the patient receiving the electrical signal.

36. The method of claim 30 wherein the generating and delivering operations are performed in response to the patient having bowel urgency associated with IBD.

37. The method of claim 30 wherein the electrical signal is delivered in discrete stimulation sessions each having a duration of between about 30 minutes and about 3 hours.

38. The method of claim 37 wherein the electrical signal is delivered during a single stimulation session per day.

39. The method of claim 37 wherein the electrical signal is delivered during two or more stimulation sessions per day.

40. A method of treating bowel urgency in a patient with Inflammatory Bowel Disease (IBD), the method comprising: programming a signal generator to generate and deliver an electrical signal to a sacral nerve of the patient via an implanted signal delivery device positioned adjacent the sacral nerve, wherein the electrical signal has a frequency within a frequency range of from about 4 Hz to about 6 Hz, a pulse width in a pulse width range of from about 400 microseconds to about 600 microseconds, and an amplitude at or above a sensation threshold of the patient, and wherein the electrical signal reduces bowel urgency in the patient.41 . The method of claim 40 wherein the frequency is about 5 Hz.

42. The method of claim 40 wherein the pulse width is about 450 microseconds.

43. The method of claim 40 wherein the patient has ulcerative colitis.

44. The method of claim 40 wherein the electrical signal reduces bowel urgency in the patient by at least 25% relative to a baseline level of bowel urgency prior to the patient receiving the electrical signal.

45. The method of claim 40 wherein the electrical signal reduces bowel urgency in the patient by at least 50% relative to a baseline level of bowel urgency prior to the patient receiving the electrical signal.

46. The method of claim 40 wherein the programming operation is performed at least partially in response to the patient having bowel urgency associated with IBD.

47. The method of claim 40 wherein the electrical signal is delivered in discrete stimulation sessions each having a duration of between about 30 minutes and about 3 hours.

48. The method of claim 47 wherein the electrical signal is delivered during a single stimulation session per day.

49. The method of claim 47 wherein the electrical signal is delivered during two or more stimulation sessions per day.

50. A sacral nerve stimulation system for treating bowel urgency in a patient with Inflammatory Bowel Disease (IBD), the system comprising: an implantable signal delivery element positionable proximate a sacral nerve of the patient; and a signal generator programmed with instructions that, when executed, cause the signal generator to generate and deliver an electrical signal to the sacral nerve of the patient via the implantable signal delivery element,wherein the electrical signal has a frequency within a frequency range of from about 4 Hz to about 6 Hz, a pulse width in a pulse width range of from about 400 microseconds to about 600 microseconds, and an amplitude at or above a sensation threshold of the patient, and wherein the electrical signal reduces bowel urgency in the patient.51 . The system of claim 50 wherein the frequency is about 5 Hz.

52. The system of claim 50 wherein the pulse width is about 450 microseconds.

53. The system of claim 50 wherein the signal generator is implantable.

54. The system of claim 50 wherein the signal generator is an external signal generator.

55. The system of claim 50 wherein the electrical signal is delivered in discrete stimulation sessions each having a duration of between about 30 minutes and about 3 hours.

56. The system of claim 55 wherein the electrical signal is delivered during a single stimulation session per day.

57. The system of claim 55 wherein the electrical signal is delivered during two or more stimulation sessions per day.

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