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 may be treated by transmitting electrical signals to one or more sacral nerves of a patient via an implanted signaling device positioned proximate to the one or more sacral nerves of the patient. In some embodiments, the electrical signal may modulate neural activity of the patient, which in turn may reduce inflammation in the patient by altering an imbalance between the sympathetic and parasympathetic systems of the patient and / or modifying a threshold of an inflammatory response in the gastrointestinal system.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 373,536, filed on August 25, 2022, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present technology relates to electrically modulating neural tissue to treat patient conditions. Background Art

[0004] Inflammatory bowel disease (IBD) is a digestive system disorder characterized by chronic inflammation of the gastrointestinal tract. IBD includes Crohn's disease that causes intermittent inflammation of the gastrointestinal tract and ulcerative colitis that causes persistent inflammation of the colon. Both Crohn's disease and ulcerative colitis cause similar patient symptoms, including patient discomfort (such as abdominal pain), gastrointestinal dysfunction (such as diarrhea) and other complications (such as fever, weight loss, etc.). IBD is typically treated with drug therapy, including anti-inflammatory drugs and immune system suppressants. In extreme cases, the patient may even undergo surgery to remove the inflamed or damaged parts of the colon or other parts of the digestive tract. However, both medicine and surgery can not cure IBD, and symptoms usually persist or recur during or after treatment. In addition, in some patients, medicine and surgery have minimal efficacy and / or cause adverse side effects. Therefore, there is a need for improved treatment of IBD.

[0005] A neurostimulation system typically has a signal generator that generates electrical pulses, and one or more signal transmission devices, such as wires, that transmit the electrical pulses to nerve tissue or muscle tissue. The transmitted electrical pulses modulate neural activity to treat the underlying patient condition. For example, neurostimulation has been used to treat a variety of conditions, 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 a variety of urological conditions, including urinary retention, urinary incontinence, and fecal incontinence. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0007] Figure 1B A patient's sacral nerve anatomy is shown, and a sacral nerve implant according to some embodiments of the present technology is shown as implanted in a representative location. Figure 1A Part of the signal transmission device of the system.

[0008] Figure 2Ais a partial schematic diagram of electrical signals generated according to some embodiments of the present technology.

[0009] Figure 2B is a partial schematic diagram of another electrical signal generated according to some embodiments of the present technology.

[0010] Figure 3A 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.

[0011] Figure 3B is another 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. DETAILED DESCRIPTION OF THE INVENTION

[0013] A. Introduction

[0014] The present technology relates to the use of neuromodulation to treat inflammatory bowel disease (IBD). For example, many embodiments described herein include one or more sacral nerves of electrical stimulation patients to treat the IBD of patients. As described in detail in the detailed description of the present invention, electrical signals can be transmitted via an implanted signal transmission device located close to one or more sacral nerves of the patient. Electrical signals can regulate the activity of sacral nerves and / or other nerves, which in turn can reduce inflammation in patients by changing the imbalance between the sympathetic nervous system and the parasympathetic nervous system of the patient and / or modifying the threshold of inflammatory response in the gastrointestinal system. Not bound by theory, it is expected that the sacral nerves of patients can be transmitted to electrical signals according to the present technology than the current treatment of IBD to select to cause less side effects and / or provide more effective treatment.

[0015] Unless otherwise indicated, the terms "generally", "about" and "approximately" refer to values ​​within 10% of the stated value. For example, the term "about 100" used refers to a range of 90 to 110 (including the end values). In the case of using relative terms to refer to things that do not include numerical values, these terms are understood by those skilled in the art as their ordinary meanings.

[0016] As used herein, and unless otherwise indicated, the terms "modulate," "modulation," and "stimulate," generally refer to electrical signals that have an inhibitory, excitatory, and / or other effect on a target neural population. Thus, a sacral nerve "stimulator" may have an inhibitory and / or excitatory effect on certain neural populations.

[0017] As used herein, the terms "electrotherapy signal," "electrical signal," "therapy signal," "signal," and other related 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).

[0018] As used herein, "proximity to 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, "proximity to the target neural population" includes but is not limited to Figure 1B The relative wire positions described and shown in , and other positions not explicitly described herein.

[0019] 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 sites of a patient and associated implantable structures for providing modulation. Although selected embodiments are described below with reference to modulating sacral nerves, the modulation may in some cases be directed to other neural structures and / or target neural populations and / or other neural tissues of the body. For example, some embodiments may include modulating the vagus nerve, splenic nerve, splanchnic nerves, and / or other peripheral nerves. Some embodiments may have different configurations, components, and / or procedures than those described herein, and other embodiments may eliminate specific components and / or procedures. Therefore, a person of ordinary skill in the relevant art will understand that the present disclosure may include other embodiments having additional elements, and / or may include embodiments without the following references. Figures 1A-3B Other embodiments of several features are shown and described.

[0020] B. Representative embodiments of the present technology

[0021] Figure 1A A sacral neuromodulation system 100 ("system 100") implanted to stimulate the sacral nerves of a patient and configured according to embodiments of the present technology is schematically illustrated. The system 100 includes a signal generator 110 and a signal delivery device 120. The signal generator 110 may be implanted subcutaneously and / or implantable within the patient P. For example, in the illustrated embodiment, the signal generator 110 is implanted subcutaneously in the lower back / upper buttock region of the patient P (e.g., adjacent to but posterior to the iliac crest IC and / or iliac fossa IF).

[0022] The signal transmission device 120 extends from the signal generator 110 and can be implanted in the patient P in proximity to a target nerve population. In some embodiments, the target nerve population includes one or more sacral spinal nerves (e.g., the S1 sacral nerve, the S2 sacral nerve, the S3 sacral nerve, and / or the S4 sacral nerve). Therefore, in some embodiments, the signal transmission device 120, when implanted, can extend through one of the sacral foramina S1-S4 (the illustrated embodiment depicts the signal transmission device 120 extending through the sacral foramina S1) and adjacent to one or more sacral spinal nerves. More specifically, the signal transmission 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 transmission device 120 can carry features configured to administer therapy to the target nerve population. For example, the signal transmission device 120 may include one or more wires or wire bodies 122 extending from the signal generator 110 toward the target nerve population (e.g., toward the S3 sacral nerve). As described with reference to Figure 1B As described in greater detail, lead 122 may include or carry one or more electrical contacts or electrodes (eg, ring electrodes, clasp electrodes, and / or other suitable electrical contacts) that transmit electrical signals to a target neural population.

[0023] In operation, the signal generator 110 may generate a signal (e.g., an electrical signal) and transmit it to the signal transmission device 120. The signal transmission device 120 may in turn transmit the electrical signal to the target neural population, for example, to electrically modulate neurons within the target neural population to induce a therapeutic effect in the patient. Figure 2A and 2B Representative electrical signals that may be generated by the signal generator 110 and transmitted to the patient P via the signal transmission device 120 are described in more detail.

[0024] The signal generator 110 may include a machine-readable (e.g., computer-readable) medium including instructions for generating and transmitting electrical signals. Thus, generating electrical signals according to the methods described herein may include executing computer-executable instructions contained by, on, or in a computer-readable medium located within the signal generator 110. The signal generator 110 may also include one or more processors, memory units, batteries (rechargeable and / or non-rechargeable), communication devices (e.g., antennas), and / or other software- or hardware-based components for executing machine-readable instructions. Figure 1A As shown, the signal generator 110 may include a single housing for storing some or all of the aforementioned components, but in other embodiments, some or all of the aforementioned components may be stored in separate housings.

[0025] 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) outside the patient P. A physician or other healthcare provider can use the physician controller to program the signal generator 110, for example, to select the parameters of the electrical signal generated by the signal generator 110. In some embodiments, the signal generator 110 can also communicate with a patient controller outside 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 can use the patient controller to start and stop the electrical stimulation therapy, and / or use the patient controller to control certain parameters (e.g., amplitude) of the electrical stimulation. In some embodiments, the signal generator 110 can transmit data to the physician controller and / or the patient controller for the user to view. For example, the signal generator 110 can 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 time), etc. The physician controller and patient controller may comprise dedicated controller devices, or may be implemented as applications on a smartphone, tablet computer, or the like.

[0026] In some embodiments, system 100 can be implanted in patient P to treat IBD or related conditions, including Crohn's disease or ulcerative colitis. For example, system 100 can transmit electrical signals to one or more sacral nerves of the patient to electrically stimulate one or more sacral nerves. As described in detail in the detailed description of the invention, electrical signals can treat, reduce and / or improve IBD. For example, electrical signals can reduce one or more IBD-related symptoms (e.g., diarrhea, abdominal pain, weight loss, etc.), and / or reduce inflammation that causes one or more symptoms. In addition, although shown as providing unilateral stimulation, in some embodiments, system 100 can be configured to provide bilateral sacral nerve stimulation to treat the patient's IBD. Refer to below Figure 2A and 2B Describes additional details of electrical signaling and stimulation protocols for treating IBD.

[0027] 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 the stimulation therapy. During the trial period, the patient P may use a temporary external trial stimulator that generates electrical signals and transmits the electrical signals to the target neural population via the signal transmission device 120 or another implanted signal transmission element. If the patient responds well during the trial period, the patient may elect to have the signal generator 110 implanted to facilitate chronic stimulation therapy. In some embodiments, the trial period may be omitted and the signal generator 110 may be implanted without the patient having previously received stimulation from a temporary external signal generator.

[0028] Figure 1B 1 is an illustration of a patient's sacral plexus SP, and a distal portion of a lead 122 shown implanted at a representative location. The sacral plexus SP includes four sacral spinal nerves: a first sacral nerve S1, a second sacral nerve S2, a third sacral nerve S3, and a fourth sacral nerve S4. The lead 122 is shown extending along (e.g., close to) the third sacral nerve S3 so that it can electrically stimulate the third sacral nerve S3. However, in other embodiments, the lead 122 can be positioned close to other sacral spinal nerves, and / or close to other neural fibers of the sacral plexus SP to electrically stimulate other target tissues. In yet other embodiments, the lead 122 can be positioned close to other neural structures of the sacral plexus SP.

[0029] Figure 1B Also shown are a plurality of electrodes or electrical contacts 124a-d carried by the lead 122, as previously described. The electrical signal generated by the signal generator 110 and transmitted by the lead 122 can be transmitted to the target neural population via the electrodes 124a-d. Although the lead 122 is shown to have four electrodes, the lead 122 can have more or fewer electrodes, such as one, two, three, four, five, six, seven, eight, or more.

[0030] In some embodiments, a test stimulus may be administered to the patient during a procedure to implant the signal transmission device 110. This may be done to ensure proper placement of the lead 122, e.g., to ensure that the electrical signal transmitted via the lead 122 is applied to the target neural population. In some embodiments, the test stimulus is applied at or above the sensory threshold during implant surgery so that the patient can provide intraoperative feedback regarding the location of the sensation and, therefore, the location of the lead 122. In some embodiments, the test stimulus is administered at or above the motor threshold during implant surgery, and the motor response to the test stimulus is observed to determine the location of the lead 122. However, in other embodiments, other techniques (e.g., imaging) may be used to confirm the placement of the lead 122, such that intraoperative test stimulation is no longer required.

[0031] Figure 2A is a partial schematic illustration of a representative electrical signal waveform 200 ("signal 200") generated according to an embodiment of the present technology. Signal 200 can be generated by the above Figure 1A and 1B The signal 200 may be generated by the described system 100 (eg, by the signal generator 110), or by another sacral neuromodulation system. As described in the detailed description of the invention, the signal 200 may be delivered to the sacral region of a patient to treat a patient condition, such as IBD.

[0032] Signal 200 includes repetitive pulse cycles 201, wherein each pulse cycle 201 has 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 to the first polarity. For example, in the illustrated embodiment, the first pulse phase 203 is an anode pulse phase and the second pulse phase 204 is a cathode pulse phase, but in other embodiments the anode pulse phase and the cathode pulse phase can be reversed so that the cathode pulse phase is the first pulse phase and the anode pulse phase is the second pulse phase. In other embodiments, signal 200 includes monophasic pulses. In such embodiments, signal 200 includes repetitive pulses of the same polarity.

[0033] 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 a baseline (e.g., zero or about zero), but in other embodiments, the amplitude of the signal 200 can be a non-zero value during the interphase interval 214. 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.

[0034] 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 the following pulse width range: 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—in some embodiments, the electrical signals described herein can have pulse width values ​​outside of the foregoing ranges.

[0035] In some embodiments, the second pulse phase 204 has the same or approximately the same pulse width as the first pulse phase 203. Thus, the second pulse phase 204 can have any pulse width described 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 can 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 can have a pulse width of 400 microseconds or less.

[0036] Regardless of whether the first pulse phase 203 and the second pulse phase 204 have the same pulse width, the total charge transferred during the second pulse phase 204 can be equal or approximately equal in magnitude and opposite in polarity to the total charge transferred during the first pulse phase 203. In this way, the second pulse phase 204 is a charge balanced pulse that prevents or at least reduces charge accumulation at the electrode used to transmit the signal 200. Therefore, in embodiments where 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 and opposite amplitudes. In embodiments where 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 so that the total charge transferred 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 unbalanced so that the first pulse phase 203 and the second pulse phase 204 do not transfer the same amount of charge. In such embodiments, the charge accumulated at the electrodes can be passively dissipated.

[0037] The interpulse interval 212 is a rest period between sequential pulses 202. During the interpulse interval 212, the signal 200 can return to a baseline amplitude (e.g., zero or approximately zero) so that little or no charge is applied to the patient. In some embodiments, the interpulse interval can be within the following interpulse interval range: 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 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 of the duration of the pulse 202. In other embodiments, the duration of the interpulse interval 212 is set based on the selected pulse 202 duration and the desired signal frequency.

[0038] 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 transmitted per second). The signal 200 may have a frequency between about 0.5 Hz and about 50 Hz. For example, the signal 200 may have a frequency within the following frequency ranges: 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, 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 can have frequency values ​​outside of the foregoing ranges.

[0039] Pulse 202 can have a current amplitude between about 0.1 mA and 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 between about 0.1 V and 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 of signal 200 (e.g., current amplitude and / or voltage amplitude) is set based on the sensory threshold and / or motor threshold of individual patients. For example, in some embodiments, pulse 202 has a peak amplitude below the sensory or perceptual threshold of the patient. In such embodiments, when signal 200 is applied, the patient cannot usually actively feel it. For example, pulse 202 can have the following amplitude: 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 at or above the sensory threshold so that the patient can perceive the signal 200 being transmitted. In some other embodiments, pulse 202 has an amplitude below the patient's motor threshold. In such embodiments, clinically discernible movement (e.g., muscle twitching) is not caused in the patient when signal 200 is applied. For example, pulse 202 can have the following amplitude: 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.

[0040] In some embodiments, the electrical signals generated according to the present technology can have one or more ramped parameters. For example, Figure 2BAn electrical signal 250 ("signal 250") having a ramped amplitude is shown in accordance with some embodiments of the present technology. Signal 250 may be generally similar to signal 200 and may 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 may be ramped such that the peak amplitude of signal 250 varies over time. In the illustrated embodiment, for example, signal 250 includes a plurality of pulses 252 (five pulses 252a-252e are shown), wherein each sequential pulse 252 has a different amplitude than the previous 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 may then be repeated. In some embodiments, signal 250 includes multiple pulses 252 at a common amplitude before ramping up or ramping down to a different amplitude (e.g., multiple pulses having an amplitude equal to the amplitude of pulse 252a are transmitted before signal 250 is ramped up or down to transmit a pulse having an amplitude equal to pulse 252b). Although shown as ramping up or down in both directions, in other embodiments, signal 250 ramps up or down in only a single direction (e.g., either increasing or decreasing in amplitude, but not both) until a maximum or minimum amplitude is reached.

[0041] In some embodiments, other parameters of signal 250 (e.g., pulse width, inter-pulse interval, frequency, etc.) may remain constant (e.g., unchanged) while the amplitude of pulse 252 is ramped. In other embodiments, one or more other parameters may be ramped in addition to the amplitude ramping. For example, in some embodiments, both the pulse width and the amplitude of pulse 252 are ramped. In such embodiments, the pulse width of pulse 252 may be ramped inversely to the amplitude, such that when the amplitude increases, the pulse width decreases, and vice versa. Furthermore, in some embodiments, pulse width, frequency, or other parameters other than amplitude are ramped.

[0042] In some embodiments, an electrical signal described herein (e.g., Figure 2A The signal 200 and Figure 2BSignal 250) is applied during a discrete stimulation session or cycle with a duration of less than 24 hours. For example, the stimulation session can 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, the 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. 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 the time periods between stimulation sessions, the patient typically does not receive any stimulation, or at least does not receive any clinically significant stimulation. The foregoing representative stimulation time 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. In some embodiments, electrical stimulation is applied for 24 hours per day.

[0043] The number and / or duration of stimulation sessions can be associated with various patient events or activities. In a first representative example, stimulation sessions can occur while the patient is eating. For example, a patient can receive one, two, three, or four 30-minute stimulation sessions per day, synchronized with when the patient eats. In a second representative example, electrical stimulation can be delivered during a single, one to six hour stimulation session per day, synchronized with (a) before sleep (b) during sleep, or (c) both (a) and (b). In a third representative example, electrical stimulation can be delivered during one or two one-hour stimulation sessions per day, synchronized with before, during, and / or after bowel movements. In another representative example, electrical stimulation can be delivered during short (e.g., 5 minute) stimulation sessions that occur once an hour while the patient is awake and / or active. For any of the foregoing examples, reference may be used. Figure 2A For signal 200 and reference Figure 2B The signal is applied for any of the signal parameters described for signal 250. The foregoing examples are also provided by way of example only—stimulation sessions may be applied at other times throughout the day, in relation to other patient events, and / or according to other intervals beyond those described above.

[0044] In some embodiments, the patient can control when they receive stimulation sessions. For example, the patient can access a patient controller that can control the signal generator (e.g., Figure 1A ) to start stimulation sessions. It may be beneficial to provide patients with control over the timing of stimulation sessions, because patients can start stimulation at convenient times and / or when patients experience IBD symptoms (or the severity of IBD symptoms increases). In a representative example, patients can choose to start stimulation sessions during the day (e.g., in contrast to the night), while avoiding certain activities (e.g., driving, time periods of concentration, etc.), and / or during or after a cycle or activity that may cause an increase in symptoms (e.g., during or after eating). In other embodiments, the signal generator may be programmed to automatically apply stimulation sessions during a predetermined interval. For example, the signal generator may be programmed to automatically transmit stimulation sessions at 1 p.m. every day or at another selected time. As another example, the signal generator may be programmed to automatically transmit stimulation sessions related to certain patient activity times. For example, the signal generator may be programmed to automatically transmit stimulation sessions at the time when the patient usually eats (e.g., 8 a.m., 12 p.m., and / or 6 p.m.). Additionally or alternatively, the signal generator may be programmed to automatically deliver stimulation sessions at times when the patient's symptoms are typically most severe, which may be determined using patient feedback such as questionnaires, symptom logs, etc. As yet another example, the signal generator may be programmed to automatically deliver stimulation sessions based on when the patient takes other medications (e.g., concurrently with, for a specified duration before, or for a specified duration after). Programming the signal generator to automatically administer stimulation sessions may be advantageous because it eliminates the possibility of a patient forgetting to initiate therapy, and may therefore provide more consistent therapy.

[0045] The electrical signal may be applied intermittently or continuously during a stimulation session. For example, the electrical signal may be applied continuously (e.g., uninterruptedly) throughout the stimulation session. Alternatively, the electrical signal may be applied intermittently so that the signal is actively transmitted only during a portion of the stimulation session. In such embodiments, the stimulation session may cycle between an "on" time when the signal is applied and an "off" time when the signal is not applied. In some embodiments, the "on" time may be between about 1 second and about 10 minutes, and the "off" time may be between about 1 second and about 10 minutes. Representative examples of suitable intermittent stimulation schedules include 10 seconds on, 10 seconds off; 10 seconds on, 30 seconds off; 10 seconds on, 60 seconds off; 10 seconds on, 90 seconds off; 30 seconds on, 30 seconds off; 30 seconds on, 60 seconds off; 30 seconds on, 90 seconds off; 1 minute on, 1 minute off; 10 minutes on, 10 minutes off, etc. The on 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 and off times.

[0046] During stimulation sessions, whether the signal is applied intermittently or continuously, the signal may be applied according to a duty cycle of about 0.1% to about 100% during each stimulation session. As used herein, and again with reference 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 inter-pulse interval 212) in which a pulse 202 is actively transmitted. That is, for a single pulse period, the duty cycle can be expressed as: (pulse width / pulse period duration) x 100. For example, if a pulse period includes (1) a biphasic pulse with no inter-phase interval and 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 next pulse period begins), the duty cycle is 1% (1 millisecond combined pulse width / 100 millisecond pulse period duration, x 100). In this way, the term "duty cycle" is distinguished from the term "intermittent", which generally refers to the continuous transmission of sequential pulse periods for a first duration (e.g., 10 seconds) followed by a quiescent period in which no pulse periods are transmitted for a second duration (e.g., 90 seconds).

[0047] In some embodiments, two or more electrical signals (e.g., reference Figure 2A Description of signal 200 and / or reference Figure 2B For example, in some embodiments, the first signal is transmitted continuously (e.g., 24 hours a day) as a base signal, and the second signal is transmitted during discrete stimulation sessions (e.g., any of the stimulation sessions described previously). The first signal and the second signal may have a reference Figure 2A and 2B Any signal parameter described for signal 200 and signal 250. However, the first signal may have a first set of signal transmission parameters (e.g., frequency, pulse width, amplitude, duty cycle, etc.), and the second signal may have a second set of signal transmission parameters, which are at least partially different from the first set of signal transmission 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 with a duty cycle of about 1%, and the second signal may be applied with a duty cycle of about 50%. The foregoing is provided only by way of example, and the first signal may be different from the second signal in other ways. In some embodiments, the second signal may be programmed to be automatically applied at various time intervals, for example, to correspond to various patient events or activities described above. In other embodiments, the second signal may be an "on-demand" signal that a patient may, for example, start in response to an increase in IBD symptoms.

[0048] In some embodiments, the first signal and the second signal are transmitted in a cycle. For example, the first signal can be applied for a first time period (e.g., a first stimulation session), and the second signal can be applied for a second time period (e.g., a second stimulation session) after the first time period. In such embodiments, the first time period can partially overlap with the second time period, although in other embodiments the first time period does not overlap with the second time period.

[0049] In some embodiments, both the first signal and the second signal are generated by the same signal generator (e.g., reference Figure 1A The first signal and the second signal may be generated by the same signal transmission device (e.g., reference signal generator 110). Figure 1A The first signal and the second signal may be administered via the same signal transmission device 120 described above or via different signal transmission devices. In embodiments where the first signal and the second signal are transmitted via the same signal transmission device, the first signal and the second signal may be transmitted by different electrodes of the same signal transmission device (e.g., so that the first signal and the second signal can be transmitted in parallel, if desired). In embodiments where the transmission of the first signal and the second signal does not overlap in time, the first signal and the second signal may be transmitted by the same electrode combination.

[0050] C. Representative activity mechanisms

[0051] The autonomic nervous system regulates many body functions, such as heart rate, digestion, respiratory rate, etc. 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 (such as proinflammatory cytokines, anti-inflammatory cytokines, etc.) to mediate inflammation. This is largely controlled by the sympathetic nervous system and the parasympathetic nervous system. When the sympathetic nervous system is activated, the release of proinflammatory substances (such as proinflammatory cytokines, such as TNF-α, IL-1, IL-18, etc.) can be induced, and the parasympathetic nervous system can induce the release of anti-inflammatory substances (such as, anti-inflammatory cytokines, such as IL-4, IL-10, etc.). Generally, the sympathetic and parasympathetic nervous systems work together to promote immune response and regulate healing. However, in some patients, the sympathetic and parasympathetic nervous systems may be unbalanced or dysfunctional, which may lead to chronic inflammation. Such patients may have a chronic imbalance between the serum levels of proinflammatory cytokines and anti-inflammatory cytokines. Examples of chronic conditions in which patients may have an imbalance between pro-inflammatory and anti-inflammatory cytokines include IBD.

[0052] The cholinergic anti-inflammatory pathway (CAP) is a neural mechanism that inhibits the release of pro-inflammatory cytokines. For example, when activated, CAP inhibits the 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 input from multiple peripheral nerves, including the vagus nerve, splenic nerve, and sacral nerves. It has been previously demonstrated that stimulation of the vagus nerve activates CAP, which in turn has been shown to reduce the production / release of pro-inflammatory cytokines and reduce inflammation.

[0053] Without being bound by theory, a potential mechanism of action supporting sacral nerve stimulation for the treatment of IBD includes activation of CAP. In some embodiments, this can occur by activating afferent nerve fibers, which can transmit signals from the sacral nerves to the brain, which in turn can activate CAP. In other embodiments, this can occur by directly activating CAP without involving the central nervous system. In any case, activating CAP can cause T cells in the spleen to release the neurotransmitter acetylcholine, which can bind to the α7 nicotinic acetylcholine receptors on the macrophages in the spleen. This can reduce the ability to release inflammatory cytokines, including, for example, TNF-α, IL-6 and / or IL-1β. Activating CAP can also cause acetylcholine to be directly released from one or more local nerves (e.g., splenic nerves, sacral nerves), bypassing the need for T cell mediation. The reduction of proinflammatory cytokines can help restore the imbalance between proinflammatory cytokines and anti-inflammatory cytokines observed in many IBD patients. This in turn may normalize the balance between the sympathetic nervous system and the parasympathetic nervous system, thereby leading to reduced inflammation and improving IBD-related symptoms.

[0054] Another potential mechanism of action involves activating the efferent nerve fibers extending from the sacral nerves to the gastrointestinal tract (e.g., colon). For example, activating the efferent nerve fibers that dominate the distal intestine can promote the release of acetylcholine from intestinal muscle neurons. Then, the secreted acetylcholine can bind to receptors (e.g., α7 nicotinic acetylcholine receptors) on macrophages close to the gastrointestinal tract. As described above, the binding of acetylcholine to the α7 receptors on macrophages can reduce the release of proinflammatory cytokines and / or block proinflammatory cytokines. The reduction of proinflammatory cytokines may alleviate gastrointestinal inflammation, leading to improvement of IBD-related symptoms.

[0055] The aforementioned mechanism of action is provided as a potential explanation for the efficacy observed in the treatment of IBD using sacral nerve stimulation. However, in addition to or in place of the mechanisms described herein, the benefits of sacral nerve stimulation in IBD patients may be produced by alternative mechanisms. For example, although the aforementioned mechanisms are primarily related to reducing and / or blocking pro-inflammatory cytokines, other mechanisms may include increasing and / or promoting anti-inflammatory cytokines. Therefore, unless otherwise expressly stated, the present technology is not limited to a specific mechanism of action.

[0056] D. Animal data

[0057] Boomerang Medical, Inc., the trustee of the present application, has conducted an animal study showing the benefits of sacral nerve stimulation to an IBD rat model. In order to conduct this study, nine Sprague-Dawley rats were anesthetized and received surgical implants of electrodes electrically connected to the third sacral nerve. During the first post-implantation time period starting 8 days after electrode implantation, 4% dextran sulfate (DSS) was applied to rats every day to induce gastrointestinal inflammation (e.g., as a model of ulcerative colitis). The rats were then divided into a first group ("test group") receiving sacral nerve stimulation during the second post-implantation time period, and a second group ("control group") not receiving stimulation during the second post-implantation time period. For the test group, stimulation was applied at a frequency of 5.2 Hz, a pulse width of 210 microseconds, and a voltage amplitude of 80-90% of the motor threshold. Stimulation was applied once a day for one hour. During the one-hour stimulation session, stimulation was applied continuously. During the first post-implantation time period and the second post-implantation time period, the disease activity index (DAI) of two groups of rats was scored every day. The DAI included ranking weight loss, stool consistency, and bleeding on a four-point scale (0, 1, 2, 3), with higher numbers in each category reflecting more severe scores. The scores for each rat were then summed to determine the rat's daily total DAI score (with a maximum daily score of 9).

[0058] Figure 3AIt is a figure 300 comparing the average daily DAI sum score of the test group (line 310) receiving daily stimulation during the second post-implantation period and the control group (line 320) not receiving daily stimulation during the second post-implantation period. More specifically, the x-axis measures the number of days after implantation, and the y-axis measures the average total DAI score. As shown, due to being administered DSS, the DAI scores of the test group and the control group increased during the first post-implantation period (labeled as "DSS" on Figure 300). After the first post-implantation period (starting from the 14th day), rats no longer receive DSS, but receive stimulation (test group) or sham stimulation (control group) during the second post-implantation period (labeled as "SNS" on Figure 300). As shown, during the second post-implantation stimulation period, the DAI scores of both the test group and the control group decreased. However, the DAI score of the test group decreased at a faster rate than the DAI score of the control group, which shows that the rats receiving stimulation recover faster from the inflammation induced by DSS.

[0059] Figure 3B is displayed in the corresponding Figure 3A The first stimulation period of the period marked as "DSS" in Figure 3A The second stimulation period is marked as "SNS" in the time period. Figure 3A Graph 350 of the "area under the curve" ("AUC") of line 310 and line 320. A larger AUC indicates a higher average DAI during the relevant time period, while a lower AUC indicates a lower average DAI during the relative time period. As shown, during the first stimulation time period when DSS was being administered to the rats but no stimulation was received, the AUC of the test group (identified by reference number 360) and the AUC of the control group (identified by reference number 370) were substantially the same. However, during the second stimulation time period when the test group received sacral nerve stimulation and the control group did not receive sacral nerve stimulation, the AUC of the test group (identified by reference number 365) was significantly lower than the AUC of the control group (identified by reference number 375). This further verifies that the test group exhibited a faster decline in AUC than the control group, reflecting that sacral nerve stimulation helps to reduce DAI scores in the IBD rat model. Without being bound by theory, Figure 3A and 3B The animal data reported in therefore support that sacral nerve stimulation may be beneficial in treating inflammatory diseases such as IBD.

[0060] E. Representative Examples

[0061] The following examples are provided to further illustrate embodiments of the present technology and should not be construed as limiting the scope of the present technology. In the context of referring to certain embodiments or their features, it is for illustrative purposes only and is not intended to limit the present technology unless otherwise stated. It should be understood that the present technology can make many changes in the procedures described herein while still remaining within the scope of the present technology. Such changes are intended to be included within the scope of the currently disclosed technology.

[0062] 1. A method of treating a patient suffering from inflammatory bowel disease (IBD), comprising:

[0063] generating an electrical signal having a frequency in the frequency range of about 1 Hz to about 10 Hz, a pulse width in the pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude less than a patient's sensory threshold; and

[0064] delivering an electrical signal to the patient's sacral nerves via an implanted signal delivery device positioned adjacent to the patient's sacral nerves,

[0065] Wherein the electrical signal is delivered continuously in stimulation sessions having a duration of between about 15 minutes to about 3 hours, and wherein the electrical signal reduces inflammation in the patient.

[0066] 2. The method of Example 1, wherein the frequency range is from about 4 Hz to about 6 Hz.

[0067] 3. The method of Example 1, wherein the frequency range is from about 4.8 Hz to about 5.2 Hz.

[0068] 4. The method of any one of examples 1-3, wherein the pulse width ranges from about 100 microseconds to about 500 microseconds.

[0069] 5. A method according to any one of Examples 1-4, wherein the amplitude is equal to or less than 90% of the sensory threshold.

[0070] 6. A method according to any one of Examples 1-4, wherein the amplitude is equal to or less than 70% of the sensory threshold.

[0071] 7. A method according to any one of Examples 1-6, wherein the electrical signal is a biphasic electrical signal.

[0072] 8. The method of any of Examples 1-7, wherein the signal delivery device comprises a unilateral lead carrying a plurality of electrodes, and wherein the plurality of electrodes are positioned proximate to the S3 sacral nerve.

[0073] 9. A method according to any one of Examples 1-8, wherein the electrical signal reduces inflammation in the patient by reducing the secretion of pro-inflammatory cytokines.

[0074] 10. The method of any one of Examples 1-8, wherein the electrical signal reduces inflammation in the patient by modulating the sympathetic and / or parasympathetic nervous systems.

[0075] 11. A method according to any one of Examples 1-9, wherein the electrical signal reduces inflammation in the patient by activating a cholinergic anti-inflammatory pathway.

[0076] 12. A method according to any one of Examples 1-11, wherein the stimulation session is a stimulation session once a day.

[0077] 13. The method of any one of Examples 1-12, wherein the generating and transmitting operations are performed in response to the patient being diagnosed with IBD.

[0078] 14. A method of treating a patient suffering from inflammatory bowel disease (IBD), comprising:

[0079] 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 between about 15 minutes and about 3 hours,

[0080] wherein the electrical signal has a frequency in the frequency range of about 1 Hz to about 10 Hz, a pulse width in the pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude less than a sensory threshold of the patient; and

[0081] wherein the electrical signal reduces inflammation in the patient.

[0082] 15. A method according to Example 14, wherein the frequency range is about 4 Hz to about 6 Hz.

[0083] 16. The method of example 14 or example 15, wherein the pulse width ranges from about 100 microseconds to about 500 microseconds.

[0084] 17. A method according to any of Examples 14-16, wherein the amplitude is equal to or less than 90% of the sensory threshold.

[0085] 18. The method of any of Examples 14-17 wherein the signal delivery device comprises a unilateral lead carrying a plurality of electrodes, and wherein the plurality of electrodes are positioned proximate to the S3 sacral nerve.

[0086] 19. A method according to any one of Examples 14-18, wherein the electrical signal reduces inflammation in the patient by reducing the secretion of pro-inflammatory cytokines.

[0087] 20. A method according to any one of Examples 14-18, wherein the electrical signal reduces inflammation in the patient by modulating the sympathetic and / or parasympathetic nervous systems.

[0088] 21. A method according to any one of Examples 14-18, wherein the electrical signal reduces inflammation in the patient by activating a cholinergic anti-inflammatory pathway.

[0089] 22. A method according to any one of Examples 14-21, wherein the stimulation sessions are stimulation sessions once a day.

[0090] 23. The method of any one of Examples 14-22, wherein the programmed operation is performed in response to the patient being diagnosed with IBD.

[0091] 24. A system for treating a patient suffering from inflammatory bowel disease (IBD), comprising:

[0092] an implantable signal transmission device positionable adjacent a sacral nerve of the patient; and

[0093] A signal generator programmed with the following instructions, when the instructions are executed, enables the signal generator:

[0094] delivering electrical signals to the patient's sacral nerves via the implanted signal delivery device during one or more stimulation sessions having a duration between about 15 minutes and about 3 hours,

[0095] wherein the electrical signal has a frequency in the frequency range of about 1 Hz to about 10 Hz, a pulse width in the pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude less than a sensory threshold of the patient; and

[0096] wherein the electrical signal reduces inflammation in the patient.

[0097] 25. A system according to Example 24, wherein the frequency range is about 4 Hz to about 6 Hz.

[0098] 26. A system according to Example 24 or Example 25, wherein the pulse width ranges from about 100 microseconds to about 500 microseconds.

[0099] 27. A system according to any of Examples 24-26, wherein the amplitude is equal to or less than 90% of the sensory threshold.

[0100] 28. The system of any of Examples 24-27 wherein the signal delivery device comprises a unilateral lead carrying a plurality of electrodes, and wherein the plurality of electrodes are positioned proximate to the S3 sacral nerve.

[0101] 29. A system according to any of Examples 24-28, wherein the electrical signal reduces inflammation in the patient by reducing the secretion of pro-inflammatory cytokines.

[0102] 30. A system according to any of Examples 24-28, wherein the electrical signal reduces inflammation in the patient by modulating the sympathetic and / or parasympathetic nervous systems.

[0103] 31. A system according to any of Examples 24-28, wherein the electrical signal reduces inflammation in the patient by activating a cholinergic anti-inflammatory pathway.

[0104] 32. A system according to any of Examples 24-31, wherein the stimulation session is a stimulation session once a day.

[0105] F. in conclusion

[0106] From the foregoing, it should be understood that the specific embodiments of the disclosed technology are described herein for the purpose of illustration, but various modifications can be made without departing from the present technology. For example, the electrical signal described herein can be transmitted with a value not explicitly disclosed herein in combination with parameter values ​​within the aforementioned range. Certain aspects of the technology described in the context of a specific embodiment can be combined or eliminated in other embodiments. In addition, although the 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 must exhibit such advantages to fall within the scope of the present technology. Therefore, the present disclosure and related technology may encompass other embodiments not explicitly shown or described herein.

[0107] The use of "and / or", such as in "A and / or B", refers to A alone, B alone, and both A and B. In addition, the term "comprising" is used throughout to refer to including at least the listed features, such that any greater number of the same features and / or additional types of other features are not excluded. It should also be understood that specific embodiments are described herein for illustrative purposes, but various modifications may be made without departing from the present technology. In addition, 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 must exhibit such advantages to fall within the scope of the technology. Therefore, the present disclosure and related technology may encompass other embodiments not explicitly shown or described herein.

[0108] When providing a numerical range, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed, accurate to one-tenth of the lower limit unit, unless the context clearly stipulates otherwise. The present disclosure covers each smaller range between any specified value or intermediate value in the specified range and any other specified value or intermediate value in the specified range. The upper and lower limits of these smaller ranges can be independently included in the range or excluded from the range, and in these smaller ranges, whether including one of the limits, excluding any limit or including each range of two limits, is also included in the present disclosure, but is subject to any clearly excluded limits in the specified range. When the specified range includes one or two limits, the scope excluding one or two of these included limits is also included in the present disclosure.

Claims

1. A method of treating a patient suffering from inflammatory bowel disease (IBD), comprising: generating an electrical signal having a frequency in a frequency range of about 1 Hz to about 10 Hz, a pulse width in a pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude less than a sensory threshold of the patient; and transmitting the electrical signal to the patient's sacral nerve via an implanted signal delivery device positioned adjacent to the patient's sacral nerve, Wherein the electrical signal is delivered continuously in stimulation sessions having a duration of between about 15 minutes to about 3 hours, and wherein 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. The method of claim 1, wherein the amplitude is equal to or less than 90% of the sensory threshold.

6. The method of claim 1, wherein the amplitude is equal to or less than 70% of the sensory threshold. The method according to claim 1 , wherein the electrical signal is a biphasic electrical signal.

8. The method of claim 1, wherein the signal delivery device comprises a unilateral lead carrying a plurality of electrodes, and wherein the plurality of electrodes are positioned proximate to the S3 sacral nerve.

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

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

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

12. The method of claim 1, wherein the stimulation sessions are once-daily stimulation sessions.

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

14. 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 the implanted signal delivery device during one or more stimulation sessions having a duration between about 15 minutes and about 3 hours, wherein the electrical signal has a frequency in the frequency range of about 1 Hz to about 10 Hz, a pulse width in the pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude less than a sensory threshold of the patient; and wherein 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. The method of claim 14, wherein the pulse width ranges from about 100 microseconds to about 500 microseconds.

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

18. The method of claim 14, wherein the signal delivery device comprises a unilateral lead carrying a plurality of electrodes, and wherein the plurality of electrodes are positioned proximate to the S3 sacral nerve.

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

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

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

22. The method of claim 14, wherein the stimulation sessions are once-daily stimulation sessions.

23. The method of claim 14, wherein the programmed operations are performed in response to the patient being diagnosed with IBD.

24. A system for treating a patient suffering from inflammatory bowel disease (IBD), comprising: an implantable signal transmission device positionable proximate to a sacral nerve of the patient; and A signal generator programmed with the following instructions, when the instructions are executed, causes the signal generator to: delivering electrical signals to the patient's sacral nerves via an implanted signal delivery device during one or more stimulation sessions having a duration between about 15 minutes and about 3 hours, wherein the electrical signal has a frequency in the frequency range of about 1 Hz to about 10 Hz, a pulse width in the pulse width range of about 50 microseconds to about 700 microseconds, and an amplitude less than a sensory threshold of the patient; and wherein the electrical signal reduces inflammation in the patient.

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

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

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

28. The system of claim 24, wherein the signal delivery device comprises a unilateral lead carrying a plurality of electrodes, and wherein the plurality of electrodes are positioned proximate to the S3 sacral nerve.

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

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

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

32. The system of claim 24, wherein the stimulation sessions are once-daily stimulation sessions.

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