Systems and methods for treating inflammatory bowel disease using neuromodulation

Abstract

Systems and methods for treating inflammatory bowel disease (IBD) using neuromodulation are described herein. For example, IBD can be treated by delivering electrical signals to one or more sacral nerves of a patient via an implanted signal delivery device positioned adjacent to one or more of the patient's sacral nerves. In some embodiments, the electrical signals can modulate neural activity in the patient, which in turn can reduce inflammation in the patient by altering the imbalance between the patient's sympathetic and parasympathetic nervous systems and / or modifying the threshold for inflammatory responses in the gastrointestinal system.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 373,536, filed August 25, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0002] (Technical field) The present technology is directed to electrically modulating neural tissue to treat patient conditions. [Background technology]

[0003] (background) 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 persistent inflammation of the colon. Both Crohn's disease and ulcerative colitis cause similar patient symptoms, including patient discomfort (e.g., abdominal pain), abnormal gastrointestinal function (e.g., diarrhea), and other complications (e.g., fever, weight loss, etc.). IBD is typically treated using pharmaceutical therapies, including anti-inflammatory drugs and immune system suppressants. In extreme cases, patients may even undergo surgery to remove inflamed or damaged portions of the colon or other parts of the digestive tract. However, neither medication nor surgery cures IBD, and symptoms often persist or recur during or after treatment. Additionally, in some patients, medications and surgery have minimal effectiveness and / or induce unwanted side effects. Therefore, there is a need for improved treatments for IBD.

[0004] Neurological stimulation systems generally include a signal generator that generates electrical pulses and one or more signal delivery devices, such as leads, that deliver the electrical pulses to neurological or muscle tissue. The delivered electrical pulses modulate neural activity, treating the underlying patient condition. For example, neurostimulation has been used to treat a variety of disorders, such as pain, mobility 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 a variety of urinary system disorders, including urinary retention, urinary incontinence, and fecal incontinence. Summary of the Invention [Means for solving the problem]

[0005] A. Introduction The present technology is directed to treating inflammatory bowel disease (IBD) using neuromodulation. For example, many of the embodiments described herein involve electrically stimulating one or more sacral nerves of a patient to treat the patient's IBD. As described in detail throughout this detailed description, the electrical signal can be delivered via an implanted signal delivery device positioned proximate to one or more of the patient's sacral nerves. The electrical signal can modulate the activity of the sacral nerves and / or other nerves, which in turn can reduce inflammation in the patient by altering an imbalance between the patient's sympathetic and parasympathetic nervous systems and / or modifying the threshold for inflammatory responses in the gastrointestinal system. Without being bound by theory, it is expected that delivering electrical signals to a patient's sacral nerves in accordance with the present technology can induce fewer side effects and / or provide more effective treatment than current treatment options for IBD. [Brief explanation of the drawings]

[0006] [Figure 1A] FIG. 1A is a partial schematic illustration of an implantable sacral neuromodulation system positioned in a patient's sacral region to deliver electrical signals, in accordance with some embodiments of the present technology.

[0007] [Figure 1B] FIG. 1B illustrates the sacral neuroanatomy of a patient, along with a portion of the signal delivery device of the system of FIG. 1A, shown as implanted in a representative location, in accordance with some embodiments of the present technology.

[0008] [Figure 2A] FIG. 2A is a partial schematic diagram of an electrical signal generated in accordance with some embodiments of the present technology.

[0009] [Figure 2B] FIG. 2B is a partial schematic diagram of another electrical signal generated in accordance with some embodiments of the present technology.

[0010] [Figure 3A] FIG. 3A is a graph depicting the results of an animal study investigating the use of sacral nerve stimulation to treat IBD, according to an embodiment of the present technology.

[0011] [Figure 3B] FIG. 3B is another graph depicting the results of an animal study investigating the use of sacral nerve stimulation to treat IBD in accordance with an embodiment of the present technology. DETAILED DESCRIPTION OF THE INVENTION

[0012] (Detailed explanation) Unless otherwise stated, the terms "generally," "about," and "approximately" refer to values ​​within 10% of the stated value. For example, use of the term "about 100" refers to a range of 90 to 110, inclusive. In instances where relative terms are used in reference to things that do not include numerical values, the terms are given their ordinary meaning to one of ordinary skill in the art.

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

[0014] As used herein, the terms “electrical therapy signal,” “electrical signal,” “therapy signal,” “signal,” and other related terms are used interchangeably and generally refer to an electrical signal, which may be characterized by one or more parameters such as frequency, pulse width, and / or amplitude.

[0015] As used herein, "proximate a target neural population" refers to the location 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 exemplary locations described and shown in FIG. 1B as well as other locations not explicitly described herein.

[0016] Specific details of certain embodiments of the present disclosure are described below with reference to methods for modulating one or more target neural populations (e.g., nerves) or regions in a patient and associated implantable structures for providing the modulation. While selected embodiments are described below with reference to modulating sacral nerves, modulation may, in some cases, target 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, splenic nerve, splanchnic nerve, and / or other peripheral nerves. Some embodiments may have different configurations, components, and / or procedures than those described herein, and other embodiments may exclude certain components and / or procedures. Those skilled in the art will therefore understand that the present disclosure may include other implementations with additional elements and / or other embodiments without some of the features shown and described below with reference to FIGS. 1A-3B.

[0017] B. Representative Embodiments of the Present Technology 1A schematically illustrates a sacral neuromodulation system 100 (“system 100”) implanted to stimulate a patient's sacral nerves and configured in accordance with an embodiment of the present technology. System 100 includes a signal generator 110 and a signal delivery device 120. Signal generator 110 can be subcutaneously implanted and / or implantable within patient P. For example, in the illustrated embodiment, signal generator 110 is implanted subcutaneously in the lumbar / upper buttock area of ​​patient P (e.g., adjacent to but posterior to the iliac crest IC and / or iliac fossa IF).

[0018] The signal delivery device 120 extends from the signal generator 110 and can be implanted within the patient P in proximity to a target nerve population. In some embodiments, the target nerve 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). Thus, in some embodiments, the signal delivery device 120 can extend through one of the sacral foramina S1-S4 (the illustrated embodiment depicts the signal delivery device 120 extending through the sacral foramina S1) and, upon implantation, adjacent to one or more sacral spinal nerves. More specifically, the signal delivery device 120 can be implanted in proximity to the S1 sacral nerve, the S2 sacral nerve, the S3 sacral nerve, and / or the S4 sacral nerve. The signal delivery device 120 can possess features configured to administer a therapy to the target nerve population. For example, the signal delivery device 120 may include one or more leads or lead bodies 122 extending from the signal generator 110 toward a target neural population (e.g., toward the S3 sacral nerve). As described in more detail with reference to FIG. 1B, the leads 122 may include or carry one or more electrical contacts or electrodes (e.g., ring electrodes, cuff electrodes, and / or other suitable electrical contacts) that deliver an electrical signal to the target neural population.

[0019] In operation, the signal generator 110 can generate and transmit a signal (e.g., an electrical signal) to the signal delivery device 120. The signal delivery device 120 can then deliver the electrical signal to a target neural population, e.g., electrically modulate neurons within the target neural population, and induce a therapeutic effect in the patient. Exemplary electrical signals that can be generated by the signal generator 110 and delivered to the patient P via the signal delivery device 120 are described in more detail below with reference to Figures 2A and 2B.

[0020] The signal generator 110 may include a machine-readable (e.g., computer-readable) medium containing instructions for generating and transmitting an electrical signal. Thus, generating an electrical signal according to the methods described herein may include executing computer-executable instructions contained thereon or within a computer-readable medium located within the signal generator 110. The signal generator 110 may also include one or more processors for executing the machine-readable instructions, memory units, batteries (rechargeable and / or non-rechargeable), communication devices (e.g., antennas), and / or other software- or hardware-based components. As shown in FIG. 1A, the signal generator 110 may include a single housing for storing some or all of the aforementioned components, although in other embodiments, some or all of the aforementioned components may be stored in separate housings.

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

[0022] In some embodiments, system 100 can be implanted within patient P to treat IBD or associated conditions, including Crohn's disease or ulcerative colitis. For example, system 100 can deliver electrical signals to one or more sacral nerves of the patient to electrically stimulate one or more sacral nerves. As described in detail throughout this detailed description, the electrical signals can treat, alleviate, and / or ameliorate IBD. For example, the electrical signals may reduce one or more IBD-related symptoms (e.g., diarrhea, abdominal pain, weight loss, etc.) and / or reduce inflammation causing one or more symptoms. Also, although shown as providing unilateral stimulation, in some embodiments, system 100 can be configured to provide bilateral sacral nerve stimulation to treat a patient's IBD. Additional details of electrical signals and stimulation magnitudes for treating IBD are described below with reference to FIGS. 2A and 2B.

[0023] In some embodiments, prior to receiving signals from the signal generator 110, the patient P undergoes a trial cycle during which the patient P receives electrical stimulation to determine whether the patient P responds appropriately to the stimulation therapy. During the trial cycle, the patient P may use a temporary external trial stimulator that generates an electrical signal and transmits it to a target neural population via the signal delivery device 120 or another implanted signal delivery element. If the patient responds appropriately during the trial cycle, the patient may elect to have the signal generator 110 implanted to facilitate chronic stimulation therapy. In some embodiments, the trial cycle can be omitted, and the signal generator 110 can be implanted without the patient previously receiving stimulation from the temporary external signal generator.

[0024] FIG. 1B is a diagram of a patient's sacral plexus SP, along with the distal portion of lead 122, shown as being implanted in 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. Lead 122 is shown extending along (e.g., adjacent to) the third sacral nerve S3 so that it can electrically stimulate the third sacral nerve S3. However, in other embodiments, lead 122 can be positioned adjacent to other sacral spinal nerves and / or adjacent to other nerve fibers in the sacral plexus SP to electrically stimulate other target tissues. In still other embodiments, lead 122 can be positioned adjacent to other neural structures in the sacral plexus SP.

[0025] 1B also shows multiple electrodes or electrical contacts 124a-d carried by lead 122, as previously described. Electrical signals generated by signal generator 110 and transmitted through lead 122 can be delivered to target neural populations via electrodes 124a-d. Although shown as having four electrodes, lead 122 can have more or fewer electrodes, such as one, two, three, four, five, six, seven, eight, or more.

[0026] In some embodiments, test stimulation may be administered to the patient during the procedure to implant the signal delivery device 110. This can be done, for example, to ensure proper placement of the lead 122 to ensure that the electrical signal delivered via the lead 122 is applied to the target neural population. In some embodiments, the test stimulation is administered at or above sensory threshold during the implantation procedure so that the patient can provide intraoperative feedback on the location of sensation, and therefore the location of the lead 122. In some embodiments, the test stimulation is administered at or above motor threshold during the implantation procedure, and the motor response to the test stimulation is observed to determine the location of the lead 122. However, in other embodiments, the location of the lead 122 can be confirmed using other techniques (e.g., imaging) so that intraoperative test stimulation is not required.

[0027] 2A is a partial schematic diagram of an exemplary electrical signal waveform 200 (“signal 200”) generated in accordance with an embodiment of the present technology. Signal 200 can be generated by system 100 described above with respect to FIGS. 1A and 1B (e.g., by signal generator 110) or by another sacral neuromodulation system. As described throughout this detailed description, signal 200 can be delivered to a patient's sacral region to treat a patient condition, such as IBD.

[0028] Signal 200 includes repeating pulse periods 201, each having a biphasic pulse 202 followed by an inter-pulse interval 212. Each pulse 202 includes a first pulse phase 203 having a first polarity followed by a second pulse phase 204 having a second polarity opposite the first polarity. For example, in the illustrated embodiment, first pulse phase 203 is an anodic pulse phase and second pulse phase 204 is a cathodic pulse phase, but in other embodiments, the anodic and cathodic pulse phases 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, signal 200 includes monophasic pulses. In such embodiments, signal 200 includes repeating pulses of the same polarity.

[0029] In some embodiments, the first pulse phase 203 is separated from the second pulse phase 204 by an inter-phase interval 208. During the inter-phase interval 208, the amplitude of the signal 200 can return to a baseline (e.g., zero or about zero), while in other embodiments, the amplitude of the signal 200 during the inter-phase interval 214 can be a non-zero value. In some embodiments, the inter-phase interval 208 is omitted, and the signal 200 transitions directly from the first pulse phase 203 to the second pulse phase 204.

[0030] The first pulse phase 203 can have a pulse width 206 within a pulse width range of 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 about 100 microseconds to about 1.5 milliseconds, or about 100 microseconds to about 1 millisecond, or about 100 microseconds to about 800 microseconds, or about 200 microseconds to about 700 microseconds, or about 200 microseconds to about 600 microseconds, or about 300 microseconds to about 700 microseconds, or about 300 microseconds to about 600 microseconds, or about 300 microseconds to about 500 microseconds, or about 400 microseconds to about 600 microseconds, or 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, and in some embodiments, the electrical signals described herein may have pulse width values ​​outside of the foregoing ranges.

[0031] In some embodiments, the second pulse phase 204 has the same or nearly the same pulse width as the first pulse phase 203. Thus, the second pulse phase 204 can have any of the pulse widths listed above for the first pulse phase 203. However, in other embodiments, 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. Similarly, 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.

[0032] Regardless of whether the first pulse phase 203 and the second pulse phase 204 have the same pulse width, the total charge delivered during the second pulse phase 204 can be equal or approximately equal in magnitude and opposite in polarity to the total charge delivered during the first pulse phase 203. In this manner, the second pulse phase 204 is a charge-balancing pulse that prevents or at least reduces charge buildup on the electrodes used to deliver the signal 200. Thus, in embodiments in which the first pulse phase 203 and the second pulse phase 204 have equal or approximately equal pulse widths, the first pulse phase 203 and the second pulse phase 204 can have equal or approximately equal, but opposite, amplitudes. 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 unequally charged such that the first pulse phase 203 and the second pulse phase 204 do not deliver the same magnitude of charge. In such embodiments, charge buildup at the electrodes can be passively dissipated.

[0033] The inter-pulse interval 212 is a quiet period between sequential pulses 202. During the inter-pulse interval 212, the signal 200 can return to a baseline amplitude (e.g., zero or about zero) so that little or no charge is administered to the patient. In some embodiments, the inter-pulse interval can be within an inter-pulse interval range of about 1 millisecond to about 1 second, such as about 5 milliseconds to about 500 milliseconds, or about 50 milliseconds to about 500 milliseconds, or about 100 milliseconds to about 300 milliseconds. The aforementioned inter-pulse interval ranges and values ​​are provided by way of example only, and in some embodiments, the electrical signals described herein may have inter-pulse interval values ​​outside the aforementioned ranges. In some embodiments, the duration of the inter-pulse interval 212 can be set independently from the duration of the pulses 202. In other embodiments, the duration of the inter-pulse interval 212 is set based on the selected pulse 202 duration and the desired signal frequency.

[0034] 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, 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 of about 0.5 Hz to about 50 Hz. For example, the signal 200 can have a frequency within a frequency range of about 1 Hz to about 40 Hz, or about 1 Hz to about 30 Hz, or about 1 Hz to about 25 Hz, or about 1 Hz to about 20 Hz, or about 1 Hz to about 15 Hz, or about 5 Hz to about 15 Hz, or about 1 Hz to about 12 Hz, or about 1 Hz to about 10 Hz, or about 2 Hz to about 8 Hz, or about 3 Hz to about 7 Hz, or about 4 Hz to about 6 Hz, or about 4.5 Hz to about 5.5 Hz, or about 4.8 Hz to about 5.2 Hz. In other embodiments, 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, 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, and in some embodiments, the electrical signals described herein may have frequency values ​​outside the foregoing ranges.

[0035] Pulse 202 can have a current amplitude of about 0.1 mA to about 20 mA. For example, in some embodiments, pulse 202 has a current amplitude within a current amplitude range of about 0.5 mA to about 15 mA, or about 1 mA to about 12 mA, or about 2 mA to about 12 mA, or about 3 mA to about 10 mA. Pulse 202 can also have a voltage amplitude of about 0.1 V to about 15 V. For example, in some embodiments, pulse 202 has a voltage amplitude within a voltage amplitude range of about 0.1 V to about 10 V, or about 0.2 V to about 8 V, or about 0.5 V to about 4 V. In some embodiments, the amplitude (e.g., current amplitude and / or voltage amplitude) of signal 200 is set based on an individual patient's sensory and / or motor threshold. For example, in some embodiments, pulse 202 has a peak amplitude below the patient's sensory or cognitive threshold. In such embodiments, the patient generally cannot actively sense signal 200 as it is being administered. For example, pulse 202 may have an amplitude that is 50% of the sensory threshold, 60% of the sensory threshold, 70% of the sensory threshold, 80% of the sensory threshold, 90% of the sensory threshold, or 95% of the sensory threshold. In other embodiments, pulse 202 has an amplitude that is at or above the sensory threshold so that the patient can perceive signal 200 being delivered. In still other embodiments, pulse 202 has an amplitude that is below the patient's motor threshold. In such embodiments, signal 200 does not induce clinically discernible movements (e.g., muscle spasms) in the patient while being administered. For example, pulse 202 may have an amplitude that is 50% of the motor threshold, 60% of the motor threshold, 70% of the motor threshold, 80% of the motor threshold, 90% of the motor threshold, or 95% of the motor threshold.

[0036] In some embodiments, electrical signals generated in accordance with the present technology can have one or more scaled parameters. For example, FIG. 2B illustrates electrical signal 250 (“signal 250”) with a scaled amplitude in accordance with some embodiments of the present technology. Signal 250 can be generally similar to signal 200 and can have any of the parameters and parameter values ​​described above in connection with signal 200. However, compared to signal 200, the amplitude of signal 250 can be scaled such that the peak amplitude of signal 250 varies over time. In the illustrated embodiment, for example, signal 250 includes multiple pulses 252 (five pulses 252a-252e are shown), with each successive pulse 252 having a different amplitude than the preceding pulse 252. More specifically, the amplitude of 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, 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 pulse 252a before signal 250 is ramped up or down to deliver a pulse with an amplitude equal to pulse 252b). Although shown as ramping bidirectionally, in other embodiments, signal 250 is ramped up or down in only a single direction (e.g., the amplitude is either increased or decreased, but not both) until a maximum or minimum amplitude is reached.

[0037] In some embodiments, other parameters of signal 250 (e.g., pulse width, inter-pulse interval, frequency, etc.) can remain constant (e.g., unchanged) as the amplitude of pulses 252 is increased or decreased. In other embodiments, one or more other parameters can be increased or decreased in addition to the amplitude being increased or decreased. For example, in some embodiments, both the pulse width and amplitude of pulses 252 are increased or decreased. In such embodiments, the pulse width of pulses 252 may be increased or decreased inversely to the amplitude, such that as the amplitude increases, the pulse width decreases, or vice versa. Also, in some embodiments, the pulse width, frequency, or other parameter is increased or decreased instead of the amplitude.

[0038] In some embodiments, the electrical signals described herein (e.g., signal 200 of FIG. 2A and signal 250 of FIG. 2B) are administered during discrete stimulation sessions or cycles having a duration of less than 24 hours. For example, a stimulation session may have a duration of about 5 minutes to about 12 hours, such as about 15 minutes to about 6 hours, or about 15 minutes to about 4 hours, or about 15 minutes to about 3 hours, or about 15 minutes to about 2 hours, or about 30 minutes to about 3 hours, or about 30 minutes to about 2 hours, or about 30 minutes to about 1.5 hours, or about 45 minutes to about 1.5 hours. In some embodiments, a stimulation session 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. A 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 the periods between stimulation sessions, the patient generally does not receive any stimulation, or at least no clinically meaningful stimulation. The foregoing exemplary stimulation period durations are provided by way of example only, and in some embodiments, the electrical signals described herein may be applied during stimulation sessions having different durations. In some embodiments, the electrical stimulation is applied over a 24-hour period per day.

[0039] The number and / or duration of stimulation sessions can be associated with various patient events or activities. In a first exemplary embodiment, stimulation sessions may occur while the patient is eating. For example, the patient may receive one, two, three, or four 30-minute stimulation sessions per day that are timed to occur while the patient is eating. In a second exemplary embodiment, electrical stimulation may be delivered during a single 1-6 hour stimulation session per day that is timed to occur (a) before sleep, (b) during sleep, or (c) both (a) and (b). In a third exemplary embodiment, electrical stimulation may be delivered during one or two 1-hour stimulation sessions per day that are timed to occur before, during, and / or after bowel movements. In yet another exemplary embodiment, electrical stimulation may be delivered during short (e.g., 5-minute) stimulation sessions that occur during each hour the patient is awake and / or active. For any of the foregoing examples, the signal can be applied using any of the signal parameters described for signal 200 with reference to Figure 2A and signal 250 with reference to Figure 2B. The foregoing examples are also provided by way of example only, and stimulation sessions can be applied at other times throughout the day, in connection with other patient events, and / or according to other intervals other than those described above.

[0040] In some embodiments, patients can control when they receive stimulation sessions. For example, patients may have access to a patient controller, which can control the operation of a signal generator (e.g., signal generator 110 shown in FIG. 1A) to initiate stimulation sessions. Providing patients with control over the timing of stimulation sessions can be beneficial because they can initiate stimulation during convenient times and / or when they experience IBD symptoms (or an increase in the severity of IBD symptoms). In an exemplary embodiment, a patient may choose to initiate a 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 (e.g., during or after consuming food) that may lead to increased symptoms. In other embodiments, the signal generator can be programmed to automatically administer stimulation sessions during predetermined intervals. For example, the signal generator can be programmed to automatically deliver a stimulation session at 1:00 PM each day 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 stimulation sessions at times when the patient typically eats meals (e.g., 8:00 AM, 12:00 PM, and / or 6:00 PM). Additionally or alternatively, the signal generator can be programmed to automatically deliver stimulation sessions at times when the patient's symptoms are typically at their worst, which may be determined using patient feedback such as questionnaires, symptom logs, etc. As yet another example, the signal generator can be programmed to automatically deliver stimulation sessions based on when the patient takes other medications (e.g., in conjunction with taking the medication, for a specified duration before taking the medication, or for a specified duration after taking the medication). Programming the signal generator to automatically administer stimulation sessions can be advantageous because it eliminates the possibility of the patient forgetting to start therapy and may therefore provide a more consistent therapy.

[0041] The electrical signal can be administered intermittently or continuously during a stimulation session. For example, the electrical signal can be administered continuously (e.g., without interruption) during the entire stimulation session. Alternatively, the electrical signal can be administered intermittently, such that the signal is actively delivered during only a portion of the stimulation session. In such embodiments, the stimulation session may cycle between "on" times during which the signal is administered and "off" times during which the signal is not administered. In some embodiments, the "on" times can be from about 1 second to about 10 minutes, and the "off" times can be from about 1 second to about 10 minutes. Representative examples of suitable intermittent stimulation schedules include 10 seconds on and 10 seconds off, 10 seconds on and 30 seconds off, 10 seconds on and 60 seconds off, 10 seconds on and 90 seconds off, 30 seconds on and 30 seconds off, 30 seconds on and 60 seconds off, 30 seconds on and 90 seconds off, 1 minute on and 1 minute off, 10 minutes on and 10 minutes off, etc. The on and off times are provided by way of example only, and in some embodiments, the electrical signals described herein may be applied according to different on and off times.

[0042] Whether the signal is administered intermittently or continuously during a stimulation session, the signal can be administered according to a duty cycle of about 0.1% to about 100% during each stimulation session. As used herein, and again referring to FIG. 2A , the term “duty cycle” refers to the percentage of a single pulse period 201 (consisting of a single pulse 202 and a single inter-pulse interval 212) during which a pulse 202 is actively delivered. That is, with respect to a single pulse period, the duty cycle can be expressed as the following: (pulse width / duration of the pulse period) × 100. For example, if a pulse period includes (1) a biphasic pulse with no inter-phase interval, with each phase of the pulse having a pulse width of 500 microseconds, followed by (2) an inter-pulse interval having a duration of 99 milliseconds (e.g., before the subsequent pulse period begins), the duty cycle is 1% (1 millisecond combined pulse width / 100 millisecond pulse period duration × 100). Thus, the term "duty cycle" differs from the term "intermittent," which generally refers to consecutively delivered sequential pulse periods 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., 90 seconds).

[0043] In some embodiments, two or more electrical signals (e.g., signal 200 described with reference to FIG. 2A and / or signal 250 described with reference to FIG. 2B) can be delivered in parallel. For example, in some embodiments, a first signal is delivered continuously as a base signal (e.g., over 24 hours per day), and a second signal is delivered during discrete stimulation sessions (e.g., any of the stimulation sessions described above). The first and second signals can have any of the signal parameters described for signals 200 and 250 with reference to FIGS. 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 differ, at least in part, from the first set of signal delivery parameters. As a first example, the first signal may have a frequency of approximately 1 Hz, and the second signal may have a frequency of approximately 5 Hz. As another example, the first signal may be applied at about a 1% duty cycle, and the second signal can be applied at about a 50% duty cycle. The foregoing is 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 above. In other embodiments, the second signal can be an "on-demand" signal that the patient can activate, e.g., in response to an increase in IBD symptoms.

[0044] In some embodiments, the first signal and the second signal are delivered cyclically. For example, the first signal can be administered for a first time period (e.g., a first stimulation session), and the second signal can be administered for a second time period (e.g., a second stimulation session) after the first time period. In such embodiments, the first time period may partially overlap with the second time period, while in other embodiments, the first time period does not overlap with the second time period.

[0045] In some embodiments, the first signal and the second signal are both generated by the same signal generator (e.g., signal generator 110 described with reference to FIG. 1A). The first signal and the second signal can be administered via the same signal delivery device (e.g., signal delivery device 120 described with reference to FIG. 1A) or via different signal delivery devices. 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 allow for parallel delivery of the first signal and the second signal, if desired). In embodiments in which the delivery of the first signal and the second signal does not overlap in time, the first signal and the second signal may be delivered by the same pair of electrodes.

[0046] C. Typical mechanism of action The autonomic nervous system regulates many bodily functions, such as heart rate, digestion, and respiratory rate. The autonomic nervous system also plays a fundamental role in mediating inflammation. For example, the autonomic nervous system can control the release of various immunomodulatory substances (e.g., pro-inflammatory cytokines, anti-inflammatory cytokines, etc.) to mediate inflammation. This is primarily controlled by the sympathetic and parasympathetic nervous systems. When activated, the sympathetic nervous system can induce the release of pro-inflammatory substances (e.g., pro-inflammatory cytokines such as TNF-α, IL-1, and IL-18), while the parasympathetic nervous system can induce the release of anti-inflammatory substances (e.g., anti-inflammatory cytokines such as IL-4 and IL-10). Normally, the sympathetic and parasympathetic nervous systems work in sync to promote immune responses and modulate healing. However, in some patients, the sympathetic and parasympathetic nervous systems can be imbalanced or dysfunctional, which can lead to chronic inflammation. Such patients may have a chronic imbalance between serum levels of pro-inflammatory and anti-inflammatory cytokines. An example of a chronic condition in which patients may have an imbalance between pro-inflammatory and anti-inflammatory cytokines includes IBD.

[0047] The cholinergic anti-inflammatory pathway (CAP) is a neural mechanism that inhibits the release of proinflammatory cytokines.For example, when activated, CAP inhibits the synthesis of certain proinflammatory molecules (e.g., TNF) in the liver and spleen, reducing the amount of circulating proinflammatory molecules.CAP receives input from multiple peripheral nerves, including the vagus nerve, splenic nerve, and sacral nerve.It has previously been demonstrated that stimulating the vagus nerve activates CAP, which in turn reduces the production / release of proinflammatory cytokines and reduces inflammation.

[0048] Without being bound by theory, one potential mechanism of action underlying the treatment of IBD using sacral nerve stimulation involves activating the CAP. In some embodiments, this may occur through activation of afferent nerve fibers that can transmit signals from the sacral nerve to the brain, which in turn may activate the CAP. In other embodiments, this may occur through direct activation of the CAP without involving the central nervous system. Nevertheless, activating the CAP may cause T cells in the spleen to release the neurotransmitter acetylcholine, which can bind to the α7 nicotinic acetylcholine receptor on macrophages in the spleen. This may reduce the ability to release pro-inflammatory cytokines, including, for example, TNF-α, IL-6, and / or IL-1β. Activating the CAP may also cause the direct release of acetylcholine from one or more local nerves (e.g., splenic nerve, sacral nerve), avoiding the need for a T cell intermediate. Reducing pro-inflammatory cytokines may help correct the imbalance between pro-inflammatory and anti-inflammatory cytokines observed in many patients with IBD. This, in turn, may normalize the balance between the sympathetic and parasympathetic nervous systems, leading to reduced inflammation and improvement of IBD-related symptoms.

[0049] Another potential mechanism of action involves the activation of efferent nerve fibers extending from the sacral nerves toward the gastrointestinal tract (e.g., colon). For example, activating efferent nerve fibers innervating the distal intestine can promote the release of acetylcholine from myenteric neurons. The secreted acetylcholine can then bind to receptors (e.g., α7 nicotinic acetylcholine receptors) on macrophages adjacent to the gastrointestinal tract. Binding of acetylcholine to α7 receptors on macrophages can reduce the release of proinflammatory cytokines and / or block proinflammatory cytokines, as explained above. Reduction of proinflammatory cytokines can reduce inflammation in the gastrointestinal tract, leading to improvement of IBD-related symptoms.

[0050] The aforementioned mechanisms of action are provided as potential explanations for the effectiveness observed when using sacral nerve stimulation to treat IBD. However, the benefits of sacral nerve stimulation in patients with IBD may occur through alternative mechanisms in addition to or instead of the mechanisms described herein. For example, while the aforementioned mechanisms primarily involve reducing and / or blocking pro-inflammatory cytokines, other mechanisms may involve increasing and / or promoting anti-inflammatory cytokines. Therefore, the present technology is not limited to a specific mechanism of action unless explicitly stated otherwise.

[0051] D. Animal Data The assignee of this application, Boomerang Medical, Inc., conducted an animal study demonstrating the benefits of sacral nerve stimulation on a rat model of IBD. To conduct the study, nine Sprague-Dawley rats were anesthetized and received a surgically implanted electrode electrically connected to the third sacral nerve. During the first post-implantation period of the first eight days following electrode implantation, the rats received 4% dextran sulfate (DSS) daily to induce gastroenteritis (e.g., as a model of ulcerative colitis). The rats were then divided into two groups: one group (the "test group") that received sacral nerve stimulation during the second post-implantation period, and a second group (the "control group") that did not receive stimulation during the second post-implantation period. For the test group, stimulation was applied at a frequency of 5.2 Hz, a pulse width of 210 ms, and a voltage amplitude of 80-90% of the motor threshold. Stimulation was applied for 1 hour once daily. During the 1-hour stimulation session, stimulation was applied continuously. Both groups of rats were scored daily based on the Disease Activity Index (DAI) during the first and second post-implantation periods. The DAI included grading weight loss, stool consistency, and bleeding severity based on a 4-point scale (0, 1, 2, 3), with higher numbers per category reflecting more severe scores. The scores for each rat were then summed to determine the rat's daily combined DAI score (with a maximum daily score of 9).

[0052] FIG. 3A is a graph 300 comparing the average daily DAI combined scores of a test group (line 310) that received daily stimulation during the second post-implantation period and a control group (line 320) that did not receive daily stimulation during the second post-implantation period. More specifically, the X-axis measures days post-implantation, and the Y-axis measures the average combined DAI score. As shown, the DAI scores for the test and control groups increased during the first post-implantation period (labeled "DSS" on graph 300) as a result of receiving DSS. After the first post-implantation period (starting on day 14), the rats no longer received DSS and instead received either stimulation (test group) or sham stimulation (control group) during the second post-implantation period (labeled "SNS" on graph 300). As shown, the DAI scores decreased for both the test and control groups during the second post-implantation period. However, the DAI scores for the test group decreased at a more rapid rate than the DAI scores for the control group, indicating that the stimulated rats recovered more rapidly from the DSS-induced inflammation.

[0053] 3B is a graph 350 showing the "area under the curve" ("AUC") for lines 310 and 320 from FIG. 3A during both the first stimulation cycle, corresponding to the cycle labeled "DSS" in FIG. 3A, and the second stimulation cycle, corresponding to the cycle labeled "SNS" in FIG. 3A. A larger AUC indicates a higher average DAI during the relevant cycle, while a lower AUC indicates a lower average DAI during the relevant cycle. As shown, during the first stimulation cycle, during which rats received DSS but no stimulation, the AUC for the test group (identified by reference numeral 360) and the AUC for the control group (identified by reference numeral 370) were generally identical. However, during the second stimulation cycle, 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 365) was significantly lower than the AUC for the control group (identified by reference number 375). This further demonstrates that the test group demonstrated a more rapid decrease in AUC than the control group, reflecting that sacral nerve stimulation contributed to a lower DAI score in this rat model of IBD. While not intending to be bound by theory, the animal data reported in Figures 3A and 3B therefore support that sacral nerve stimulation may be beneficial in treating inflammatory diseases such as IBD.

[0054] E. Representative Examples The following examples are provided to further illustrate the embodiments of the present technology and shall not be construed as limiting the scope of the present technology.As long as certain embodiments or their features are described, this is only for illustrative purposes and is not intended to limit the present technology unless otherwise specified.It should be understood that many variations can be made in the procedures described herein and still remain within the boundaries of the present technology.Such variations are intended to be included within the scope of the disclosed technology. Example 1: A method of treating a patient suffering from inflammatory bowel disease (IBD), comprising: generating an electrical signal having a frequency within a frequency range of about 1 Hz to about 10 Hz, a pulse width within a pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude below the patient's sensory threshold; delivering an electrical signal to the patient's sacral nerve via an implanted signal delivery device positioned adjacent to the patient's sacral nerve; Including, The electrical signal is delivered continuously over a stimulation session having a duration of about 15 minutes to about 3 hours, and the electrical signal reduces inflammation in the patient. (Example 2) The method according to Example 1, wherein the frequency range is from about 4 Hz to about 6 Hz. (Example 3) The method described in Example 1, wherein the frequency range is from about 4.8 Hz to about 5.2 Hz. (Example 4) The method of any of Examples 1-3, wherein the pulse width ranges from about 100 microseconds to about 500 microseconds. (Example 5) The method described in any of Examples 1-4, wherein the amplitude is equal to or less than 90% of the sensory threshold. (Example 6) The method described in any of Examples 1-4, wherein the amplitude is equal to or less than 70% of the sensory threshold. (Example 7) The method of any of Examples 1-6, wherein the electrical signal is a biphasic electrical signal. (Example 8) A method described in any of Examples 1-7, wherein the signal delivery device includes a unidirectional lead carrying multiple electrodes, the multiple electrodes being positioned in proximity to the S3 sacral nerve. (Example 9) The method of any of Examples 1-8, wherein the electrical signal reduces inflammation in the patient by reducing secretion of pro-inflammatory cytokines. (Example 10) The method of any of Examples 1-8, wherein the electrical signal reduces inflammation in a patient by modulating the sympathetic and / or parasympathetic nervous system. (Example 11) The method of any of Examples 1-9, wherein the electrical signal reduces inflammation in the patient by activating the cholinergic anti-inflammatory pathway. (Example 12) The method described in any of Examples 1-11, wherein the stimulation session is one stimulation session per day. (Example 13) The method of any of Examples 1-12, wherein the acts of generating and delivering are performed in response to the patient being diagnosed with IBD. Example 14: A method of treating a patient suffering from inflammatory bowel disease (IBD), comprising: programming the signal generator to deliver electrical signals to the patient's sacral nerves via the implanted signal delivery device during one or more stimulation sessions having a duration of from about 15 minutes to about 3 hours; the electrical signal has a frequency within a frequency range of about 1 Hz to about 10 Hz, a pulse width within a pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude that is below the patient's sensory threshold; The electrical signal reduces inflammation in the patient. (Example 15) The method described in Example 14, wherein the frequency range is about 4 Hz to about 6 Hz. (Example 16) The method described in Example 14 or Example 15, wherein the pulse width ranges from about 100 microseconds to about 500 microseconds. (Example 17) The method described in any of Examples 14-16, wherein the amplitude is equal to or less than 90% of the sensory threshold. (Example 18) A method described in any of Examples 14-17, wherein the signal delivery device includes a unidirectional lead carrying multiple electrodes, the multiple electrodes being positioned in proximity to the S3 sacral nerve. (Example 19) The method of any of Examples 14-18, wherein the electrical signal reduces inflammation in the patient by reducing secretion of pro-inflammatory cytokines. (Example 20) The method of any of Examples 14-18, wherein the electrical signal reduces inflammation in a patient by modulating the sympathetic and / or parasympathetic nervous system. (Example 21) The method of any of Examples 14-18, wherein the electrical signal reduces inflammation in the patient by activating the cholinergic anti-inflammatory pathway. (Example 22) The method described in any of Examples 14-21, wherein the stimulation session is one stimulation session per day. (Example 23) The method described in any of Examples 14-22, wherein the programming operation is performed in response to the patient being diagnosed with IBD. Example 24: A system for treating a patient suffering from inflammatory bowel disease (IBD), comprising: an implantable signal delivery device positionable adjacent to a sacral nerve of the patient; a signal generator programmed with instructions; Equipped with The instructions, when executed, cause the signal generator to deliver electrical signals to the patient's sacral nerves via the implanted signal delivery device during one or more stimulation sessions having a duration of from about 15 minutes to about 3 hours; the electrical signal has a frequency within a frequency range of about 1 Hz to about 10 Hz, a pulse width within a pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude that is below the patient's sensory threshold; The electrical signals reduce inflammation within the patient, the system said. (Example 25) A system described in Example 24, wherein the frequency range is about 4 Hz to about 6 Hz. (Example 26) A system described in Example 24 or Example 25, wherein the pulse width range is from about 100 microseconds to about 500 microseconds. (Example 27) A system described in any of Examples 24-26, wherein the amplitude is equal to or less than 90% of the sensory threshold. (Example 28) A system described in any of Examples 24-27, wherein the signal delivery device includes a unidirectional lead carrying multiple electrodes, the multiple electrodes being positioned in proximity to the S3 sacral nerve. (Example 29) A system described in any of Examples 24-28, wherein the electrical signal reduces inflammation in the patient by reducing the secretion of pro-inflammatory cytokines. (Example 30) A system described in any of Examples 24-28, wherein the electrical signal reduces inflammation in a patient by modulating the sympathetic and / or parasympathetic nervous system. (Example 31) A system described in any of Examples 24-28, wherein the electrical signal reduces inflammation in a patient by activating the cholinergic anti-inflammatory pathway. (Example 32) A system described in any of Examples 24-31, wherein the stimulation session is one stimulation session per day.

[0055] F. Conclusion From the foregoing, it should be understood that specific embodiments of the disclosed technology have been described herein for illustrative purposes, and that various modifications may be made without departing from the present technology. For example, the electrical signals described herein can be delivered at combinations of parameter values ​​within the aforementioned ranges at values ​​not explicitly disclosed herein. Certain aspects of the technology described in the context of particular embodiments may be combined or eliminated in other embodiments. Furthermore, 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 necessarily need to exhibit such advantages to fall within the scope of the present technology. Thus, the present disclosure and associated technology can encompass other embodiments not explicitly shown or described herein.

[0056] 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 features, but not excluding any greater number of the same features and / or other features of additional types. Also, it should be understood that specific embodiments are described herein for illustrative purposes, and that various modifications can be made without departing from the technology. Furthermore, while advantages associated with certain embodiments of the technology are described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments necessarily need to exhibit such advantages to fall within the scope of the technology. Thus, the present disclosure and related technology can encompass other embodiments not explicitly shown or described herein.

[0057] Where a range of values ​​is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limits of that range is also specifically disclosed, unless the context clearly dictates otherwise. Each smaller range between any stated or intervening value in a stated range and any other stated or intervening value within that stated range is also 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, whether or not either or both of its limits are included in the smaller range, is also encompassed within the disclosure, subject to any specifically excluded limits in the stated range. When a stated range includes one or both of its limits, ranges excluding either or both of those included limits are also included in the disclosure.

Claims

1. 1. A method of treating a patient suffering from inflammatory bowel disease (IBD), comprising: generating an electrical signal having a frequency within a frequency range of about 1 Hz to about 10 Hz, a pulse width within a pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude below the sensory threshold of the patient; delivering the electrical signal to the patient's sacral nerve via an implanted signal delivery device positioned adjacent the patient's sacral nerve; Including, The method wherein the electrical signal is delivered continuously over a stimulation session having a duration of about 15 minutes to about 3 hours, and the electrical signal reduces inflammation in the patient.

2. The method of claim 1 , wherein the frequency range is from about 4 Hz to about 6 Hz.

3. The method of claim 1 , wherein the frequency range is from about 4.8 Hz to about 5.2 Hz.

4. The method of claim 1 , wherein the pulse width ranges from about 100 microseconds to about 500 microseconds.

5. 10. The method of claim 1, wherein the amplitude is less than or equal to 90% of the sensory threshold.

6. 10. The method of claim 1, wherein the amplitude is less than or equal to 70% of the sensory threshold.

7. The method of claim 1 , wherein the electrical signal is a biphasic electrical signal.

8. The method of claim 1 , wherein the signal delivery device includes a unidirectional lead carrying multiple electrodes, the multiple electrodes being positioned in proximity to the S3 sacral nerve.

9. 10. The method of claim 1, wherein the electrical signal reduces inflammation in the patient by reducing secretion of pro-inflammatory cytokines.

10. 10. The method of claim 1, wherein the electrical signal reduces inflammation in a patient by modulating the sympathetic and / or parasympathetic nervous system.

11. 10. The method of claim 1, wherein the electrical signal reduces inflammation in the patient by activating a cholinergic anti-inflammatory pathway.

12. 10. The method of claim 1, wherein the stimulation session is one stimulation session per day.

13. 10. The method of claim 1, wherein the acts of generating and delivering are performed in response to the patient being diagnosed with IBD.

14. 1. A method of treating a patient suffering from inflammatory bowel disease (IBD), comprising: programming a signal generator to deliver electrical signals to the patient's sacral nerves via an implanted signal delivery device during one or more stimulation sessions having a duration of from about 15 minutes to about 3 hours; the electrical signal has a frequency within a frequency range of about 1 Hz to about 10 Hz, a pulse width within a pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude that is below the sensory threshold of the patient; The electrical signal reduces inflammation in the patient.

15. The method of claim 14, wherein the frequency range is from about 4 Hz to about 6 Hz.

16. 15. The method of claim 14, wherein the pulse width ranges from about 100 microseconds to about 500 microseconds.

17. 15. The method of claim 14, wherein the amplitude is less than or equal to 90% of the sensory threshold.

18. 15. The method of claim 14, wherein the signal delivery device includes a unidirectional lead carrying multiple electrodes, the multiple electrodes being positioned in proximity to the S3 sacral nerve.

19. 15. The method of claim 14, wherein the electrical signal reduces inflammation in the patient by reducing secretion of pro-inflammatory cytokines.

20. 15. The method of claim 14, wherein the electrical signal reduces inflammation in a patient by modulating the sympathetic and / or parasympathetic nervous system.

21. 15. The method of claim 14, wherein the electrical signal reduces inflammation in the patient by activating the cholinergic anti-inflammatory pathway.

22. 15. The method of claim 14, wherein the stimulation session is one stimulation session per day.

23. 15. The method of claim 14, wherein the programming operation is performed in response to the patient being diagnosed with IBD.

24. 1. A system for treating a patient suffering from inflammatory bowel disease (IBD), comprising: an implantable signal delivery device positionable adjacent to a sacral nerve of the patient; a signal generator programmed with instructions; Equipped with the instructions, when executed, cause the signal generator to deliver electrical signals to the patient's sacral nerves via the implanted signal delivery device during one or more stimulation sessions having a duration of from about 15 minutes to about 3 hours; the electrical signal has a frequency within a frequency range of about 1 Hz to about 10 Hz, a pulse width within a pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude that is below the sensory threshold of the patient; The electrical signal reduces inflammation in the patient.

25. 25. The system of claim 24, wherein the frequency range is from about 4 Hz to about 6 Hz.

26. 25. The system of claim 24, wherein the pulse width range is from about 100 microseconds to about 500 microseconds.

27. 25. The system of claim 24, wherein the amplitude is less than or equal to 90% of the sensory threshold.

28. 25. The system of claim 24, wherein the signal delivery device includes a unidirectional lead carrying multiple electrodes, the multiple electrodes positioned in proximity to the S3 sacral nerve.

29. 25. The system of claim 24, wherein the electrical signal reduces inflammation in the patient by reducing secretion of pro-inflammatory cytokines.

30. 25. The system of claim 24, wherein the electrical signal reduces inflammation in a patient by modulating the sympathetic and / or parasympathetic nervous system.

31. 25. The system of claim 24, wherein the electrical signal reduces inflammation in the patient by activating the cholinergic anti-inflammatory pathway.

32. 25. The system of claim 24, wherein the stimulation session is one stimulation session per day.

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