Sacral Neuromodulation for Bowel and Sexual Function

Abstract

Provided herein is a method of inducing colon contraction / defecation or penile erection in a patient, the method comprising stimulating one or more sacral roots of the patient's spinal cord with a plurality of electrical pulses, the electrical pulses being delivered at a frequency of about 3 Hz to about 10 Hz or about 10 Hz to about 80 Hz.

Description

[Technical field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 255,606, filed October 14, 2021, which is incorporated by reference in its entirety.

[0002] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with Government support under Grant No. N66001-20-C-4050 awarded by the Department of Defense / Defense Advanced Research Projects Agency. The Government has certain rights in the invention.

[0003] FIELD OF THEINVENTION Provided herein are methods and associated devices for stimulating the sacral spinal cord / sacral roots, and more particularly, methods for regulating bowel and sexual function by stimulating the sacral spinal cord / sacral roots, and devices for carrying out such methods. [Background technology]

[0004] Related Field Description Many conditions arise from the disturbance of normal physiological processes in the lower pelvis. Among these conditions are urinary incontinence, overactive bladder, urinary retention and voiding dysfunction, urethral sphincter dysfunction, fecal incontinence, constipation, irritable bowel syndrome, sexual dysfunction in both sexes, premature ejaculation, decreased sexual sensation, anorgasmia, urethral pain, prostatic pain, vulvar pain, anal pain, rectal pain, and bladder pain. These conditions may arise from neurological disorders, or other diseases or conditions, such as spinal cord injury or stroke, trauma, disease (e.g., multiple sclerosis), and / or congenital defects.

[0005] In the past, such conditions have been treated with sacral anterior root stimulation, which requires extensive spinal surgery to expose the sacral roots for implantation of stimulating electrodes. Although sacral dorsal rhizotomy prevents anal sphincter contractile dysfunction, it also abolishes spinal reflex defecation and sexual functions such as penile erection. Thus, there is a need for a minimally invasive neuromodulation approach that does not require invasive spinal surgery and sacral dorsal rhizotomy. Summary of the Invention

[0006] Provided herein is a method of inducing colonic contractions and / or defecation in a patient, the method comprising stimulating one or more sacral roots of the patient's spinal cord and / or one or more sacral segments of the patient's spinal cord with a plurality of electrical pulses, wherein the electrical pulses are delivered at a frequency of about 3 Hz to about 10 Hz.

[0007] Also provided herein is a method of inducing penile erection in a patient, comprising stimulating one or more sacral roots of the patient's spinal cord and / or one or more sacral segments of the patient's spinal cord with a plurality of electrical pulses, wherein the electrical pulses are delivered at a frequency of about 10 Hz to about 80 Hz.

[0008] Further non-limiting embodiments are presented in the following sections. Item 1. A method of inducing colonic contractions and / or defecation in a patient, comprising stimulating one or more sacral roots of the patient's spinal cord and / or one or more sacral segments of the patient's spinal cord with a plurality of electrical pulses, wherein the electrical pulses are delivered at a frequency of about 3 Hz to about 10 Hz.

[0009] Clause 2. The method of clause 1, wherein the one or more sacral roots or segments are one or more of the patient's S1, S2, S3, S4, and / or S5 sacral roots or segments.

[0010] Clause 3. The method of clause 1 or clause 2, wherein the patient is a human.

[0011] Clause 4. The method of any of clauses 1-3, wherein one or more sacral roots or segments of the patient's spinal cord innervates the patient's colon and rectum.

[0012] Clause 5. The method of any of clauses 1 to 4, wherein the stimulation is applied to the ventral / anterior and / or dorsal / posterior sacral spinal roots.

[0013] Clause 6. The method of any of clauses 1 to 5, wherein the stimulation is applied to the patient's S2 and / or S3 sacral roots and / or sacral spinal segments.

[0014] Clause 7. The method of clause 6, wherein the stimulation is applied to the patient's S2 and / or S3 ventral / anterior sacral spinal roots.

[0015] Clause 8. The method of any of clauses 1 to 7, wherein the stimulation is applied at a frequency of about 7 Hz.

[0016] Clause 9. The method according to any one of clauses 1 to 8, wherein the stimulation is applied at an intensity capable of inducing colonic / rectal contractions in the range of about 0.1 V to about 20 V and / or about 0.1 mA to about 20 mA.

[0017] Clause 10. The method of clause 9, wherein the stimulus is applied at an intensity of about 1 V and / or 1 mA.

[0018] Clause 11. The method of clause 9, wherein the stimulus is applied at an intensity of about 4 V and / or 4 mA.

[0019] Clause 12. The method of clause 9, wherein the stimulus is applied at an intensity of about 6V and / or 6mA.

[0020] Clause 13. The method according to any one of clauses 1 to 12, wherein the stimulation is applied continuously or intermittently.

[0021] Clause 14. The method of clause 13, wherein the intermittent stimulation is applied for about 1 minute followed by about 1 minute of no stimulation being applied.

[0022] Paragraph 15. A method of inducing penile erection in a patient, comprising stimulating one or more sacral roots of the patient's spinal cord and / or one or more sacral segments of the patient's spinal cord with a plurality of electrical pulses, wherein the electrical pulses are delivered at a frequency of about 10 Hz to about 80 Hz.

[0023] Clause 16. The method of clause 15, wherein the one or more sacral roots or segments is one or more of the patient's S1, S2, S3, S4, and / or S5 sacral roots or segments.

[0024] Clause 17. The method of clause 15, wherein the patient is a human.

[0025] Clause 18. The method of any of clauses 15-17, wherein one or more sacral roots or segments of the patient's spinal cord innervates the patient's penis.

[0026] Clause 19. The method of any of clauses 15 to 18, wherein the stimulation is applied to the ventral / anterior and / or dorsal / posterior sacral spinal roots.

[0027] Clause 20. The method of any of clauses 15 to 19, wherein the stimulation is applied to the S1 and / or S2 sacral roots and / or sacral spinal segments.

[0028] Clause 21. The method of clause 20, wherein the stimulation is applied to the S1 and / or S2 ventral / anterior sacral spinal roots.

[0029] Clause 22. The method of any of clauses 15 to 21, wherein the stimulation is applied at a frequency of about 30 Hz to about 40 Hz.

[0030] Clause 23: The method according to any one of clauses 15 to 22, wherein the stimulation is applied at an intensity capable of inducing penile contraction in the range of about 0.1 V to about 20 V and / or about 0.1 mA to about 20 mA.

[0031] Clause 24. The method of clause 23, wherein the stimulus is applied at an intensity of about 3 V and / or 3 mA.

[0032] Clause 25. The method of clause 23, wherein the stimulus is applied at an intensity of about 6V and / or 6mA.

[0033] Clause 26. The method according to any one of clauses 15 to 25, wherein the stimulation is applied continuously or intermittently.

[0034] Clause 27. The method of any one of clauses 15 to 26, wherein the stimulation produces a pressure increase in the patient's corpus cavernosum of at least 50 cmH2O.

[0035] Clause 28. The method of any of clauses 15 to 27, wherein the stimulation produces a pressure increase in the patient's corpus cavernosum of at least 100 cmH2O.

[0036] Clause 29. A system for inducing colon contractions and / or defecation in a patient, comprising: at least one lead configured to be placed proximate to one or more sacral roots of the patient's spinal cord and / or one or more sacral segments of the patient's spinal cord; a pulse generator in electrical communication with the at least one lead; and at least one processor in communication with the pulse generator, the processor being programmed or configured to cause the pulse generator to deliver one or more electrical pulses through the at least one lead at a frequency of about 3 Hz to about 10 Hz.

[0037] Clause 30. The system of clause 29, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses through the at least one lead at a frequency of about 7 Hz.

[0038] Clause 31. The system of clause 29 or clause 30, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses through the at least one lead at an intensity capable of inducing colonic / rectal contractions in the range of about 0.1 V to about 20 V and / or about 0.1 mA to about 20 mA.

[0039] Clause 32. The system of any of clauses 29-31, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses at an intensity of about 1 V and / or 1 mA through the at least one lead.

[0040] Clause 33. The system of any of clauses 29-32, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses at an intensity of about 4 V and / or 4 mA through the at least one lead.

[0041] Clause 34. The system of any of clauses 29-33, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses at an intensity of about 6 V and / or 6 mA through the at least one lead.

[0042] Clause 35. The system of any of clauses 29-34, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses continuously or intermittently through the at least one lead.

[0043] Clause 36. The system of any of clauses 29-35, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead for about one minute followed by about one minute of not applying stimulation.

[0044] Clause 37. A system for inducing penile contraction in a patient, comprising: at least one lead configured to be placed proximate to one or more sacral roots of the patient's spinal cord and / or one or more sacral segments of the patient's spinal cord; a pulse generator in electrical communication with the at least one lead; and at least one processor in communication with the pulse generator, the processor being programmed or configured to cause the pulse generator to deliver one or more electrical pulses through the at least one lead at a frequency of about 10 Hz to about 80 Hz.

[0045] Clause 38. The system of clause 37, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses through the at least one lead at a frequency of about 30 Hz to about 40 Hz.

[0046] Clause 39. The system of clause 37 or clause 38, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses through the at least one lead at an intensity capable of inducing a penile erection, in the range of about 0.1 V to about 20 V and / or about 0.1 mA to about 20 mA.

[0047] Clause 40. The system of any of clauses 37-39, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses at an intensity of about 3 V and / or 3 mA through the at least one lead.

[0048] Clause 41. The system of any of clauses 37-40, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses at an intensity of about 6 V and / or 6 mA through the at least one lead.

[0049] Clause 42. The system of any of clauses 37-41, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses continuously or intermittently through the at least one lead. [Brief description of the drawings]

[0050] [Figure 1A] 1A-C are schematic diagrams of various embodiments of an external system (FIGS. 1A and 1B), as well as an implantable system (FIG. 1C), for use in stimulating spinal roots and / or the spinal cord, as described herein. [Figure 1B] 1A-C are schematic diagrams of various embodiments of an external system (FIGS. 1A and 1B), as well as an implantable system (FIG. 1C), for use in stimulating spinal roots and / or the spinal cord, as described herein. [Figure 1C] 1A-C are schematic diagrams of various embodiments of an external system (FIGS. 1A and 1B), as well as an implantable system (FIG. 1C), for use in stimulating spinal roots and / or the spinal cord, as described herein. [Diagram 2] FIG. 2 illustrates an experimental setup for electrically stimulating the sacral roots S1, S2, or S3 to induce colonic contractions according to non-limiting embodiments described herein. [Diagram 3] FIG. 3 shows distal and proximal colonic responses to stimulation of the sacral S1-S3 ventral roots at various frequencies (1-50 Hz). Panel A. S1 ventral root. Panel B. S2 ventral root. Panel C. S3 ventral root. Data were obtained from the same animal. [Figure 4A]Figures 4A and B show that distal and proximal colon responses to sacral ventral root stimulation depend on frequency and spinal segment. Figure 4A, Panel A. S1 ventral root. Figure 4A, Panel B. S2 ventral root. Figure 4B. S3 ventral root. Contraction amplitudes evoked by different stimulation frequencies in different sacral segments are normalized to the maximum response in the same animal. S2 ventral root stimulation intensities (4-16 V) were 1.5-3 times the threshold intensity of 7 Hz stimulation to evoke observable contractions of the proximal colon. In cases where S1 and S3 ventral root stimulation did not evoke colon contractions, different frequencies were tested using the maximum stimulation intensity (8-12 V) that did not evoke lower body movements. * = significantly different from 1 Hz (one-way ANOVA); # = significantly different from S2 ventral root (two-way ANOVA). N = 7 cats. [Figure 4B] Figures 4A and B show that distal and proximal colon responses to sacral ventral root stimulation depend on frequency and spinal segment. Figure 4A, Panel A. S1 ventral root. Figure 4A, Panel B. S2 ventral root. Figure 4B. S3 ventral root. Contraction amplitudes evoked by different stimulation frequencies in different sacral segments are normalized to the maximum response in the same animal. S2 ventral root stimulation intensities (4-16 V) were 1.5-3 times the threshold intensity of 7 Hz stimulation to evoke observable contractions of the proximal colon. In cases where S1 and S3 ventral root stimulation did not evoke colon contractions, different frequencies were tested using the maximum stimulation intensity (8-12 V) that did not evoke lower body movements. * = significantly different from 1 Hz (one-way ANOVA); # = significantly different from S2 ventral root (two-way ANOVA). N = 7 cats. [Diagram 5]Figure 5 shows distal and proximal colon responses to intermittent (5 x 1 min) or prolonged (5 min) continuous stimulation of both the S2 ventral and dorsal roots. Panel A. Pressure traces showing distal and proximal colon contractions. The intensity threshold (T) for proximal colon contractions was 4 V, and 6 V (1.5 T) was used to elicit intermittent or continuous contractions. Panel B. Summary of results (N = 4 cats) showing that contraction amplitude was maintained during intermittent stimulation (7 Hz, 0.2 ms, 1.5-4 T, T = 2-4 V). Panel C. Summary of results (N = 7 cats) showing that maximum contraction amplitude was significantly reduced from a mean of 30 cmH2O to approximately 18 cmH2O at the end of continuous 5 min stimulation (7 Hz, 0.2 ms, 1.5-3 T, T = 2-4 V). * = significantly different (p < 0.05, paired t-test). [Figure 6] Figure 6 shows defecation induced by stimulation of the S2 ventral and dorsal roots. Panel A. In cat #1, after insertion of three marbles into the rectum, defecation induced by sacral S2 root stimulation resulted in the expulsion of two marbles after 1 and 2 min of stimulation, respectively, with the last marble being partially expelled during the last 2 min of the 6 min stimulation. Panel B. In cat #2, after insertion of one marble into the rectum, defecation occurred 2.5 min after stimulation. After insertion of four marbles, over 11 min of stimulation, defecation occurred at 4.5 min, with three marbles remaining in the rectum. Colonic contraction pressures were measured with a large condom catheter, with the proximal and distal colon covered with condoms. [Figure 7] FIG. 7 illustrates an experimental setup for electrical stimulation of the sacral spinal roots S1, S2, or S3 to induce penile erection according to non-limiting embodiments described herein. [Figure 8]FIG. 8 shows penile pressure in the corpus cavernosum evoked by electrical stimulation of the sacral ventral root at different frequencies and different spinal segments. Panel A. In one cat, brief (1 min) S1 ventral root stimulation (10-80 Hz) evoked an increase in penile pressure (200 cmH2O) that lasted several minutes after the end of stimulation. Panel B. In another cat, brief (1 min) S2 ventral root stimulation (30-80 Hz) was most effective in eliciting a large increase in penile pressure (150 cmH2O). Panel C. Spinal segment effect on penile pressure evoked by electrical stimulation of the ventral root. *=significantly different from S1 ventral root (p<0.05, ANOVA). Stimulation: 30 Hz, 0.6-12 V, 0.2 ms. Panel D. Frequency effect on penile pressure evoked by stimulation of S1 or S2 ventral root. * = significantly different from 5 Hz (p < 0.05, ANOVA). Stimulus: 0.6–12 V, 0.2 ms. [Figure 9] FIG. 9 shows penile pressure in the corpus cavernosum induced by prolonged (10 min) electrical stimulation of the sacral roots (both ventral and dorsal roots). Panel A. In one cat, S1 spinal root stimulation induced a large increase in penile pressure (160 cmH2O) that was maintained for the 10 min of stimulation. Panel B. In another cat, S2 spinal root stimulation gradually increased penile pressure for the first 9 min, then produced a rapid pressure rise in the last minute of stimulation, reaching a penile pressure of 140 cmH2O at the end of stimulation. Panel C. On average (N=8 cats), penile pressure at the end of the 10 min of stimulation was maintained at the same level as the maximum pressure produced during stimulation. [Figure 10]FIG. 10 shows cavernosal penile pressure induced by prolonged (10 min) electrical stimulation of the sacral spinal roots (both ventral and dorsal roots) before and after complete spinal cord transection at the T9-T10 level. Panel A. S1 spinal root stimulation in cats before spinal cord transection induced a maximum increase in penile pressure of 175 cmH2O, which was then maintained at a high pressure during the 10 min stimulation. Panel B. In the same cat, S1 spinal root stimulation 10 min after spinal cord transection induced a small (30 cmH2O) increase in penile pressure in the first 3 min, followed by a rapid increase in pressure reaching a maximum penile pressure of 150 cmH2O. Panel C. On average (N=6 cats), the maximum penile pressure induced by sacral S1 / S2 root stimulation was significantly decreased by acute spinal cord transection. *Significant difference (p=0.0025, paired t-test). Description of the Invention

[0051] The use of numerical values ​​in the various ranges specified in this application is described as approximations, as if the word "about" preceded both the minimum and maximum values ​​in the described range, unless expressly indicated otherwise. In this manner, slight variations above and below the described ranges can be used to achieve substantially the same results as the values ​​within the range. Also, unless otherwise indicated, the disclosure of these ranges is intended as a continuous range including every value between the minimum and maximum values. For the definitions provided herein, these definitions refer to forms, synonyms, and grammatical variations of those words or phrases.

[0052] The figures attached to this application are representative in nature and should not be construed as implying a particular scale or orientation unless otherwise indicated. For purposes of the following description, the terms "upper", "lower", "right", "left", "vertical", "horizontal", "top", "bottom", "horizontal", "vertical" and their derivatives shall refer to the present invention when oriented as indicated in the drawing figures. However, it should be understood that the present invention may assume various alternative modifications and sequences of steps unless otherwise expressly indicated. Accordingly, specific dimensions and other physical characteristics relating to the embodiments disclosed herein are not to be considered limiting.

[0053] As used herein, the term "comprising" and similar terms are open ended. The term "consisting essentially of" limits the scope of a claim to those materials or steps recited and that do not materially affect the basic novel characteristics of the claimed invention. The term "consisting of" excludes any element, step, or ingredient not recited in the claim.

[0054] As used herein, the terms "a" and "an" refer to one or more.

[0055] As used herein, the term "patient" refers to any mammal, including a human, and a "human patient" is any human being.

[0056] As used herein, the terms "communication" and "communicating" refer to the receipt, transmission, or transmission of one or more signals, messages, commands, or other types of data. A unit or device communicating with another unit or device means that the unit or device can receive data from and / or transmit data to the other unit or device. The communication can use a direct or indirect connection and can be wired and / or wireless in nature. Furthermore, two units or devices can be in communication with each other even if the transmitted data can be modified, processed, routed, etc. between the first unit or device and the second unit or device. For example, a first unit can be in communication with a second unit even if the first unit passively receives data and does not actively transmit data to the second unit. As another example, a first unit can be in communication with a second unit if an intermediary unit processes data from a unit and transmits the processed data to the second unit. It will be understood that many other configurations are possible. Any known electronic communications protocol and / or algorithm known to those skilled in the art may be used, such as, for example, TCP / IP (including HTTP and other protocols), WLAN (including 802.1 la / b / g / n and other radio frequency based protocols and methods), analog transmission, GSM (Global System for Mobile Communications), 3G / 4G / LTE, BLUETOOTH, ZigBee, EnOcean, TransferJet, Wireless USB, etc.

[0057] As used herein, "electrical communication," as used herein, for example with respect to the transmission of electrical pulses from a pulse generator to an electrode, refers to the transmission of electrical pulses generated by a pulse generator, typically via conductive leads such as wires, to a skin surface electrode, electrode lead, magnetic coil, or similar device capable of generating an electrical current to stimulate a nerve or neuron, as described herein.

[0058] As used herein, "intensity threshold" (T) refers to the minimum intensity capable of eliciting a desired physiological response, such as colon / rectal contraction, defecation, or penile erection, and / or the minimum intensity capable of eliciting a contraction in the proximal portion of the colon and / or an increase in pressure in the colon or corpus cavernosum.

[0059] The "intensity" of an electrical pulse refers to and is proportional to the voltage (V) and / or current (e.g., milliamps or mA) applied to a nerve or neuron, with increases in intensity being proportional to increases in voltage or current applied to the nerve or neuron. One of ordinary skill in the art will recognize that, in terms of intensity, 1V is approximately equal to 1mV, assuming an electrode-tissue resistance of 1kΩ.

[0060] US Pat. No. 8,805,510 is incorporated herein by reference in its entirety.

[0061] Provided herein are methods of stimulating a patient's sacral spinal cord / sacral roots to induce a physiological response, particularly colon / rectal contraction and / or defecation, and devices / systems useful for implementing such methods. Also provided herein are methods of stimulating a patient's sacral spinal cord / sacral roots to induce a physiological response, particularly penile erection, and devices / systems useful for implementing such methods. Useful stimulation may be electrical, via an implanted pulse generator, or non-invasive, via a transcutaneous method, such as transcutaneous electrical stimulation. Useful stimulation may also be non-invasive, via a magnetic stimulation device that can be placed near or applied to the exterior surface of the body to induce electrical currents within the body to stimulate the spinal roots / spinal cord, for example, by using a conductive coil outside the body to generate a magnetic field to induce electrical currents in the target of interest. The methods and devices / systems disclosed herein are superior to other methods / systems, such as stimulation of the ventral roots (e.g., in animals), at least because such other methods require more invasive electrode placement.

[0062] The electrical stimulation described herein can include electrical pulses that can have any suitable characteristics, so long as the stimulation is effective to achieve a desired physiological response. Thus, the terms "electrical stimulation" and "electrical pulse" are used interchangeably herein. As will be appreciated by those skilled in the art, the characteristics of the electrical pulses, including but not limited to, amplitude (referring to the pulse strength, magnitude or size of the signal voltage or current), voltage, amperage, duration (e.g., pulse width), frequency, polarity, phase, and the relative timing and symmetry of the positive and negative pulses in biphasic stimulation, and / or waveform (e.g., square wave, sine wave, triangle wave, sawtooth wave, or variations or combinations thereof), can be varied to provide a desired physiological response. Modulation of the pulse frequency will achieve a desired physiological response as long as other characteristics of the electrical signal (e.g., but not limited to, amplitude, voltage, amperage, duration, polarity, phase, the relative timing and symmetry of the positive and negative pulses in biphasic stimulation, and / or waveform) are within a useful range.

[0063] One characteristic of the electrical signal used to produce the desired response as described above is the frequency of the electrical pulses. Effective ranges (e.g., frequencies that can produce the described effects) may vary from subject to subject, with the governing factor being achieving the desired outcome, but certain non-limiting exemplary ranges may be as follows: In non-limiting embodiments where the desired physiological response is defecation (e.g., colonic contractions), the frequency does not exceed 10 Hz. In non-limiting embodiments or aspects, the stimulation is delivered at a frequency of about 1 Hz to about 10 Hz, about 3 Hz to 10 Hz, about 5 Hz to about 10 Hz, about 7 Hz to 10 Hz, about 5 Hz, about 7 Hz, or any subrange or value therebetween. In non-limiting embodiments where the desired physiological response is penile erection, useful frequencies are in the range of about 10 Hz to about 80 Hz, optionally about 20 Hz to about 70 Hz, optionally about 20 Hz to about 50 Hz, optionally about 30 Hz to about 50 Hz, optionally about 30 Hz to about 40 Hz, optionally about 30 Hz, optionally about 40 Hz (including all values ​​and subranges therebetween). In non-limiting embodiments, the electrical pulses are delivered with a pulse width of about 0.2 milliseconds.

[0064] As indicated above, a characteristic of an electrical pulse is its intensity, which in a medium with stable or relatively stable resistance, such as mammalian tissue, can be characterized as related to current (I, typically measured in mA) or voltage (V, typically measured in mV or V) based on Ohm's law. It should thus be understood that the intensity of a stimulus is a matter of both V and I, and thus, as the intensity of the stimulus increases, both increase, e.g., proportionally or substantially proportionally. Thus, one characteristic of a pulse is the current applied to produce a physiological response. Stimulation can be achieved in typical ranges of 0.01 mA to 20 mA and / or 0.1 V to 20 V, including all subranges and values ​​therebetween.

[0065] Another characteristic of the pulse strength is the voltage. Stimulation can be achieved in the typical range of 1 mV to 20 V, including all subranges and values ​​therebetween. In non-limiting embodiments or aspects, stimulation is delivered in electrical pulses having a voltage of about 0.8 V to about 16 V, about 2 V to about 16 V, about 4 V to about 16 V, about 6 V to about 16 V, about 0.9 V, about 1 V, about 2 V, about 3 V, about 4 V, about 6 V, or any subrange or value thereof.

[0066] As discussed above, the intensity threshold (T) of the electrical pulse delivered during stimulation can be defined as the minimum intensity capable of inducing a desired physiological response, such as colon / rectal contraction, defecation, or penile erection, and / or the minimum intensity capable of inducing contraction in the proximal portion of the colon, and / or an increase in pressure in the colon or corpus cavernosum. Relative to the threshold, useful ranges for the intensity of the electrical pulse that can be delivered can include about 1T to about 4T, about 1.5T to about 3T, about 1T, about 1.5T, about 3T, about 4T, or any subrange or value therebetween. In non-limiting embodiments, the intensity of the electrical pulse is 1.5T or 2T or 2.5T or 3T.

[0067] As indicated above, the waveform of the pulses can be varied so long as the desired physiological response is achieved. Those skilled in the art will recognize that other types of electrical stimulation can also be used in accordance with the present invention. Monophasic or biphasic stimulation, or mixtures thereof, may be used. Damage to the nerve due to application of electrical current can be minimized by applying biphasic pulses or waveforms to the nerve, as opposed to monophasic pulses or waveforms that may potentially damage the nerve with prolonged use, as known in the art. "Biphasic current", "biphasic pulse", or "biphasic waveform" refers to two or more pulses of opposite polarity that have equal or substantially equal net charge (hence biphasic charge balanced) and may be symmetrical, asymmetrical, or substantially symmetrical. This can be accomplished, for example, by applying one or more positive pulses through the electrodes, followed by one or more negative pulses, typically of the same amplitude and duration as the positive pulses, or vice versa, such that the net charge applied to the target of the electrodes is zero or near zero. For charge-balanced biphasic stimulation, the pulses of opposite polarity may have different amplitudes, profiles, or durations, as long as the net applied charge from a biphasic pulse pair (combination of a positive and negative pulse) is near zero.

[0068] The waveform may be any useful shape, including, but not limited to, a sine wave, a square wave, a rectangular wave, a triangular wave, a sawtooth wave, a linear wave, a pulse wave, an exponential wave, a truncated exponential wave, or a damped sine wave. The pulses may increase or decrease during the stimulation period. In some embodiments, the waveform is rectangular. The pulses may be applied continuously or intermittently as needed. For example, the stimulation may be applied at short intervals (e.g., 1-10 minutes) or at longer intervals (360 minutes, or even longer, e.g., days, weeks, months, or even years) to achieve a longer-lasting physiological response on an hourly, daily, weekly, monthly, or yearly basis. In some embodiments, the stimulation is applied for at least 5 minutes. In non-limiting embodiments, the stimulation is applied for about 1 minute at 1 minute intervals (e.g., 1 minute of stimulation followed by 1 minute of no stimulation). In non-limiting embodiments, the stimulation is delivered until the full 5 minutes of stimulation have been delivered. In non-limiting embodiments, a period of continuous stimulation is followed by intermittent stimulation. In a non-limiting embodiment or aspect, the stimulus is delivered only when a physiological response is desired.

[0069] As described above, stimulation may be applied intermittently during a continuous or interval stimulation protocol (i.e., pulses are alternately turned on and off during any duration of stimulation interval). For example, stimulation may be applied 5 seconds on and 5 seconds off, for example, over an interval of 1-10 minutes or longer (e.g., hours, days, weeks, months, years). Another example of intermittent application of pulses may be 1-90 seconds on and 1-90 seconds off for a period of up to 360 minutes. For example, intermittent application of pulses may be continuous for as long as the pulses have the desired effect and as long as the patient desires (i.e., not painful or harmful to the patient). In one aspect, stimulation is provided continuously, for example, to treat severe symptoms or symptoms that do not respond to intermittent short-term stimulation to the extent desired by the clinician or patient.

[0070] Stimulation as described herein can be applied to the sacral roots and / or sacral cord of the patient's spinal cord to produce a desired physiological response. In a non-limiting embodiment, the desired physiological response is colon / rectal contraction and / or defecation. In a non-limiting embodiment, the desired physiological response is penile erection. In a non-limiting embodiment or aspect, the patient has a spinal cord injury or suffers from a condition such as constipation, optionally chronic constipation. Without wishing to be bound by theory, constipation, such as chronic constipation, is relieved by stimulating contraction of the colon / rectum by the methods described herein. In a non-limiting embodiment or aspect, the S1, S2, S3, S4, and / or S5 sacral roots and / or sacral cord are stimulated with pulses having parameters as described herein. One skilled in the art will recognize that the particular sacral roots and / or spinal cord segments stimulated will vary depending on the desired physiological response, as well as the patient's attributes, in particular the patient's species. For example, in the examples shown below, cats are used as experimental subjects, and those skilled in the art will recognize that the sacral roots of cats may differ from those of humans. See, for example, Toossi et al., Comparative neuroanatomy of the lumbosacral spinal cord of the rat, cat, pig, monkey, and human. Scientific Reports, 2021, 11(1955). Thus, while a physiological response may be generated in cats by stimulating the S1, S2, and / or S3 ventral roots, dorsal roots, or both, those skilled in the art will recognize that the human equivalent may be identified by different terms (e.g., anterior roots, dorsal roots, or both) and may include stimulation of different roots, since the human spinal cord includes the S4 and S5 sacral roots, but the cat spinal cord does not. Furthermore, the S1 roots of cats may correspond to different roots in humans. Those skilled in the art will recognize that the key is to target one or more sacral roots that innervate the target tissue / organ of interest (e.g., colon or penis).

[0071] In non-limiting embodiments, the desired physiological response is defecation (e.g., colonic contractions), the patient is human, and the S1, S2, S3, S4, and / or S5 ventral roots are stimulated. In non-limiting embodiments, only the S2 root is stimulated, optionally both the ventral / anterior roots and the dorsal / posterior roots, optionally only the ventral / anterior S2 root is stimulated. In non-limiting embodiments, the patient is human, and the S1-S3 ventral / anterior roots and dorsal / posterior roots are stimulated.

[0072] In non-limiting embodiments, the desired physiological response is penile erection, the patient is human, and the S1, S2, S3, S4, and / or S5 anterior roots are stimulated. In non-limiting embodiments, only the S1 root is stimulated, optionally both the ventral / anterior root and the dorsal / posterior root, and optionally only the ventral / anterior S2 root. In non-limiting embodiments, the patient is human, and the S1 and S2 roots are stimulated, optionally both the ventral / anterior root and the dorsal / posterior root. In non-limiting embodiments, the patient is human, and the S1-S3 ventral / anterior root and the dorsal / posterior root are stimulated. In non-limiting embodiments, the physiological result is measured by an increase in pressure in the corpus cavernosum of the penis or as a resultant pressure. In non-limiting embodiments or aspects, the stimulation creates an increase in pressure within the patient's corpus cavernosum of at least 25, at least 50, at least 100, at least 125, and / or at least 150 cmH2O (including all values ​​and subranges therebetween). In non-limiting embodiments or aspects, the stimulation creates pressure within the patient's corpus cavernosum that reaches at least 100, at least 125, and / or at least 150 cmH2O (including all values ​​and subranges therebetween).

[0073] Turning to the drawings, devices are also provided herein for applying stimulation with parameters as described herein in a manner sufficient to elicit a desired physiological response. FIG. 1A shows a general schematic diagram of a non-limiting embodiment or aspect of an electrical stimulation device 10 useful in aspects of the methods described herein. The device 10 includes a power source or pulse generator 20. The power source / pulse generator 20 may be fixed output or may be adjustable within a useful range, for example as described herein. The device 10 includes a first conductive lead 30 and a first nerve cuff 31, and a second conductive lead 35 having a second nerve cuff 36. The conductive leads 30 and 35 may be combined into a single lead to connect the nerve cuffs 31 and 36. In an embodiment (not shown), the nerve cuffs 31 and 36 may also be combined into a single cuff, or they may be removed entirely and replaced with a conductive metal / electrode disposed on the conductive leads 30 and 35, or on a single lead combining both 30 and 35. The conductive leads 30, 35 may be wired directly to the power source / pulse generator 20 or may include multiple leads and electrical connectors, fasteners, terminals, or clips to create a continuous electrical connection between the power source / pulse generator 20 and each of the nerve cuffs. A nerve 37 is also depicted. Skin 38 is also shown, thus the device 10 is external and may be a handheld or body worn device, held in place by a belt or strap, such as by a hook and loop fastener band, although in some embodiments the device 10 may be an implanted device (described in more detail below). In FIG. 1A, the leads are of opposite polarity and together form a circuit for applying any of the electrical waveforms described herein. Alternative designs having different leads, probes, electrodes, or electrical contacts, or combinations thereof, will be apparent to one of skill in the art. As used herein, "electrical contact" encompasses any structure useful for applying an electrical current directly to a nerve or tissue of a patient, such as the patient's skin. Structures for generating a magnetic field and thus generating an electrical current by induction are not considered electrical contacts.However, in some embodiments, any inductive probe, i.e., a structure capable of generating a magnetic field that can generate an electric current, can be used to generate the electrical pulses described herein.

[0074] Figure IB shows a schematic of another embodiment of a stimulation device 10 with an external power source similar to that of Figure IA. In Figure IB, reference numbers corresponding to those of Figure IA refer to like elements of device 10. However, surface electrodes 31a and 36a replace nerve cuffs 31 and 36 of Figure IA, and stimulation is transcutaneous. In another embodiment, not shown, surface electrodes 31a and 36a are replaced by electromagnets for magnetically induced stimulation of impulses of nerve 37.

[0075] FIG. 1C shows a further embodiment of an implanted neurostimulator 110, including an implantable housing 112. Commercially available implantable stimulators are known to those skilled in the art, such as those from Medtronic (Dublin, IE), and may be useful for the purposes set forth herein, so long as they can be programmed to deliver stimulation as set forth herein. The housing 112 contains various subunits of the device, including a power supply / pulse generator 120 connected to a first lead 130 connected to a first nerve cuff 131, and a second lead 135 connected to a second cuff 136 for stimulating a nerve 137. Skin 138 is depicted to illustrate the condition. The conductive leads 130 and 135 may be combined into a single lead to connect the nerve cuffs 131 and 136. As noted above, in multiple embodiments (not shown), nerve cuffs 131 and 136 may also be combined into a single cuff, or they may be removed entirely and replaced with conductive metal / electrodes located on leads 130 and 135, or on a single lead combining both 130 and 135. For monopolar stimulation, one of the cuffs / electrodes may be disposed on housing 112. The housing may be constructed of any biocompatible material as known in the medical arts for use in such implantable devices, such as plastic, metal, carbon fiber, or ceramic materials, or polymeric coated materials, such as metal or plastic housings coated with biocompatible polymers or hydrogels. Housing 112 also contains various connected subunits of device 110, including processor 140, memory module 142 including transient data storage (e.g., RAM), and non-transient data storage, such as flash memory or solid state drive, and optionally, battery 144, which may be recharged by magnetic induction.The processor 140 may also be connected to a wireless communication module 150 for wireless communication with an external computer or computer network, such as a smartphone, tablet, laptop, personal computer, smartwatch, workstation, server, or computer network, for example, by short-range wireless communication, or by BLUETOOTH, ZigBee, Z-wave, Wi-Fi, or over a cellular network.

[0076] The device of Fig. 1A-C may be battery powered, and optionally the battery is rechargeable. When the device is implanted, the device may be recharged wirelessly, for example by magnetic induction recharging methods, as is known. The device of Fig. 1A-C may also include a communication interface, such as a wireless communication interface or module, for transmitting data and receiving instructions from another computing device, such as a smartphone, tablet, laptop, personal computer, workstation, server, or controller app or software on a computer network. As will be appreciated by those of ordinary skill in the art of computer engineering and software engineering, numerous potential device and system configurations and implementation schemes may be used to control devices and systems that provide electrical stimulation as described herein.

[0077] Referring to FIG. 1C, which is equally applicable to any embodiment of the device, such as device 10 of FIG. 1A and / or FIG. 1B, the device 110 includes a controller for performing functions related to the electrical pulse output of the power source. In some examples, the controller is a central processing engine including a baseline processor, memory, and communication capabilities. For example, the controller may be any suitable processor including computer-readable memory and configured to execute instructions stored on the memory or received from other sources. The computer-readable memory may be, for example, a disk drive, a solid-state drive, an optical drive, a tape drive, a flash memory (e.g., a non-volatile computer storage chip), a cartridge drive, and a control element for loading new software.

[0078] In some examples, the controller includes a program, code, set of instructions, or combination thereof executable by a processor to independently or collectively instruct the devices to interact and operate in a programmatic manner, referred to herein as "programming instructions." In some examples, the controller is configured to instruct the power source / pulse generator to initiate electrical pulses and control output parameters of the power source in a manner sufficient to stimulate the sacral spinal cord / roots. One skilled in the art will recognize that the processor associated with the devices 10, 110 disclosed herein may be programmed to deliver stimulation as generally described throughout this disclosure. In either case, the controller is configured to receive and process electrical pulse parameters programmed into the device or from an external source, and optionally output data obtained from the power source as feedback to determine whether the power source is producing the desired output. Processing may include applying filters and other techniques to remove signal artifacts, noise, baseline waveforms, or other items from the captured signal to improve readability.

[0079] Further to the above, the device 10, 110 can include programming instructions that, when executed by the processor 140, cause the power supply / pulse generator 120 to apply electrical stimulation at an intensity that provides a desired physiological response as described herein. These parameters are described above, but can include stimulation at 1 Hz to 80 Hz, at an intensity of 0.01 mA to 20 mA, and / or 0.01 V to 20 V, for durations in seconds to minutes, hours, days, or continuous or intermittent stimulation (including all subranges therebetween for all parameters). EXAMPLES

[0080] Example 1 The experimental protocol and animal use in this study were approved by the University of Pittsburgh Institutional Animal Care and Use Committee.

[0081] material and method A total of nine cats (four females and five males, 4.0 ± 0.3 kg; Liberty Research, Waverly, NY) were anesthetized with isoflurane (2–5% in oxygen) during surgery and then switched to α-chloralose anesthesia (65 mg / kg iv initially, supplemented as needed) during data collection. A catheter was placed in the left cephalic vein for fluid infusion. A tracheotomy was performed and intubated to secure an airway. A catheter was placed in the right carotid artery to monitor systemic blood pressure. Heart rate and blood oxygen were monitored by a tongue-mounted pulse oximeter (9847V; NONIN Medical, Plymouth, MN). An abdominal incision was made and one balloon catheter (G15766, Cook Urological, Spencer, IN) measuring 1.4 cm in diameter and 5 cm in length was inserted into the proximal colon through a small incision at the proximal end of the colon (Figure 2). A second balloon catheter of the same size was inserted into the distal colon via the anus. In the first group of seven cats, two balloons were filled with water (5-7 ml) to provide a resting pressure of 10-15 cmH2O and proximal and distal colonic contractions were measured. In the second group of two cats, a large condom balloon catheter (3.5 cm diameter, 15 cm length) was inserted through a small incision at the proximal end of the colon and occupied the entire colon to record both proximal and distal colonic contractions. The condom was filled with water (60-70 ml) to provide a resting pressure of 10-15 cmH2O. In these two cats, one to four glass marbles (1.5 cm diameter) were also inserted via the anus into the rectum to allow video recording of expulsion of these marbles simultaneously with colonic pressure recording.

[0082] The spinal cord was exposed from lumbar L7 to sacral S3 by dorsal laminectomy. The dura was opened and each root from S1 to S3 was identified. The dorsal and ventral roots were separated and either the ventral root was stimulated individually or both the dorsal and ventral roots were stimulated together. During the experiment, the animal was in a prone position and the spinal incision was kept open with a surgical retractor, forming a pool filled with warm (35-37°C) mineral oil. The body temperature of the animal was maintained at 35°C to 37°C using a heating pad. Stimulation was performed on each sacral root by slightly lifting the spinal root above the spinal cord using a stainless steel bipolar hook electrode (electrode spacing 2-3 mm).

[0083] In the first group of seven cats, stimulation (7 Hz frequency, 0.2 ms pulse width, 1 min duration) was applied at different intensities (1–16 V) to individual sacral ventral roots (S1, S2, or S3) via hook electrodes to determine the intensity threshold (T) that elicits an observable pressure increase in the proximal colon. The colonic response to different stimulation frequencies (1–50 Hz) was then examined using the intensity (1.5–3 T) that elicited maximal colonic contractions. If stimulation to individual ventral roots did not elicit colonic contractions, the frequency response was examined using the maximal stimulation intensity that did not produce any movement of the animal's lower body. It was the intention of this study not to immobilize the hip joints and lower spine, as sacral root stimulation with hook electrodes may produce localized movements of the tail or hind limbs. However, the maximal stimulation intensity was limited by movements of the lower spine that would displace the hook electrode from the nerve. After stimulating each ventral root, the S2 ventral root that induced the largest colonic contraction was combined with the S2 dorsal root, and the combination was stimulated at the most effective frequency (7 Hz). The combined S2 root stimulation (1 min duration) was applied 5 times with 1 min intervals, followed by 5 min of continuous stimulation to determine the fatigue of colonic contractions.

[0084] In a second group of two cats, we stimulated (7 Hz) a combination of the S2 ventral and dorsal roots at an intensity that induced maximal colonic contractions for various durations (2.5-11 min) to determine whether the stimulation could induce defecation, i.e., expulsion of a marble inserted into the rectum. Defecation induced by S2 root stimulation was videotaped and the time at which the marble was expelled was recorded on a colonic pressure recording.

[0085] To compare colonic contractions induced by stimulating different ventral roots at different frequencies, the contraction amplitude was always normalized to the maximum contraction amplitude induced by stimulation in the same animal. Colonic contractions induced by 1 min of repeated stimulation were normalized to the maximum contraction amplitude induced during repeated simulations to determine reproducibility. Fatigue during continuous prolonged stimulation was determined by comparing the maximum contraction amplitude induced during 5 min of continuous stimulation with the contraction amplitude at the end of 5 min of stimulation. Data from different animals were averaged and presented as mean ± SE. Statistical significance (p < 0.05) was determined by paired t-test or repeated measures ANOVA followed by Dunnett's multiple comparisons (one-way) or Bonferroni multiple comparisons (two-way).

[0086] result Stimulation of the S2 ventral root induced larger colonic contractions than stimulation of the S1 or S3 ventral roots, with the most effective stimulation frequency being 7–10 Hz (Figures 3–4B). Figure 3 shows distal and proximal colonic pressure traces recorded from the same cat. Stimulation of the S2 ventral root induced colonic contractions in excess of 20 cmH2O at frequencies between 7 and 30 Hz, with similar contraction amplitudes in the distal and proximal colon (Figure 3, panel B). Stimulation of the S1 or S3 ventral roots did not evoke colonic contractions larger than small (<10 cmH2O) rhythmic baseline colonic contractions that occurred asynchronously during the stimulation period (Figure 3, panels A and C). In this cat, the stimulation intensity used for S2 ventral root stimulation was twice the threshold intensity used during 7 Hz stimulation to induce observable proximal colonic contractions. Because colonic responses to S1 and S3 ventral root stimulation were weak, maximal stimulation intensities just below the threshold for eliciting lower spinal column movements were applied to these roots. Movements of the hind limbs (mainly S1 / S2 stimulation) and / or tail (mainly S2 / S3 stimulation) were evoked by stimulation of each of the three roots. Figure 3 summarizes the results from seven cats showing that S2 ventral root stimulation at 7–10 Hz was optimal for producing colonic contractions that were significantly (p<0.05) larger than contractions evoked by S1 or S3 ventral root stimulation. There were no significant differences in contraction amplitudes between the distal and proximal colon (Figures 4A–4B).

[0087] Stimulation of the S2 ventral and dorsal roots together (7 Hz) induced large amplitude (>20 cmH2O) contractions in both the distal and proximal colon (Figure 5). Panel A of Figure 5 shows that intermittent 1-min stimulation at 1.5 times the threshold intensity for inducing proximal colon contractions produced stronger contractions during the second stimulation period, and the large amplitude contractions were maintained through the next three 1-min stimulations. However, the contraction amplitude gradually decreased during the 5-min continuous stimulation, indicating fatigue of the colonic contractions (Figure 5, Panel A). On average, the contraction amplitude of both distal and proximal colons was maintained during five intermittent 1-min stimulations (N=4 mice, Figure 5, Panel B), but significantly (p<0.05) decreased from the mean maximum amplitude of 30 cmH2O to approximately 18 cmH2O at the end of the 5-min continuous stimulation (N=7 mice, Figure 5, Panel C).

[0088] Stimulation of the S2 ventral and dorsal roots together induced colonic contractions of maximal amplitude of 60 cmH2O in cat #1 (Figure 6, panel A) and 40 cmH2O in cat #2 (Figure 6, panel B). In cat #1, after insertion of three marbles into the rectum, S2 root stimulation (7 Hz, 6 V, 0.2 ms) induced successful defecation with expulsion of the first marble 1 min after stimulation and the second marble 2 min after stimulation (Figure 6, panel A). Expulsion of the third marble, initiated during the last 2 min of the 6 min stimulation, was incomplete (Figure 6, panel A). In cat #2, after insertion of one marble into the rectum, S2 root stimulation (7 Hz, 6 V, 0.2 ms) induced expulsion of the marble 2.5 min after stimulation (Figure 6, panel B). However, after inserting four marbles into the rectum, only one of the four marbles was stimulated to expel after 4.5 min of stimulation, and three marbles were in the rectum at the end of 11 min of stimulation (Fig. 6, panel B). Stimulation of the S2 ventral and dorsal roots together resulted in the expulsion of only one or two marbles in these two cats, whereas stimulation of only the S2 ventral root without the dorsal root resulted in the successful expulsion of all four marbles in two cats.

[0089] Consideration The present studies in anesthetized cats show that the colonic response to sacral root stimulation depends on the stimulation frequency and the spinal segment stimulated. S2 ventral root stimulation at 7 Hz is optimal for inducing contractions of both the proximal and distal colon (Figures 3-4B). Stimulating the S2 ventral and dorsal roots together is also effective in inducing colonic contractions (Figure 5, panel A), and intermittent stimulation (1 min on, 1 min off) is more fatigue-resistant than continuous stimulation (Figure 5, panels B and C). More importantly, defecation can be induced by S2 spinal root stimulation (Figure 6).

[0090] These results have important implications for developing new neuromodulatory devices to restore defecation function in humans after SCI. Stimulation of the entire S2 spinal root (ventral and dorsal) was as effective as stimulation of the ventral root alone (Figure 4A-B) and successfully induced defecation (Figure 5), suggesting that sacral dorsal rhizotomy is not necessary, and stimulating the sacral root instead of the ventral root may be effective in restoring defecation function after SCI in humans. The main reason for performing sacral dorsal rhizotomy is to eliminate detrusor-sphincter dysregulation (DSD), which can generate high pressure in the bladder and cause renal damage. However, high blood pressure in the colon and / or rectum may not be as harmful as high blood pressure in the bladder, which can cause renal failure. If colorectal pressure is high enough to overcome anal sphincter contraction dysfunction, feces should be expelled. Furthermore, recent studies in cats have developed an effective method to temporarily inhibit sphincter activity by blocking the conduction of the clitoral nerve using electrical stimulation at 40 kHz. This method is effective in treating DSD in spinal cord injured cats, and may also be applicable to treat defecation dyssynergia when colorectal contractions are not strong enough to overcome anal sphincter dyssynergia. Thus, the new neuromodulation device may prevent DSD and / or defecation dyssynergia by stimulating the sacral roots instead of the ventral roots and simultaneously blocking the conduction of the clitoral nerve, restoring bladder function as well as defecation function after SCI. The significance of stimulating the sacral roots instead of the ventral roots is the possibility of adopting a minimally invasive surgical approach to stimulation. The S1-S3 spinal roots can be accessed by percutaneously inserting a hole needle to place the stimulation lead electrode. This surgical approach is commonly used in sacral neuromodulation therapy for overactive bladder.

[0091] Stimulation of the S2 ventral root resulted in the expulsion of all four marbles, whereas stimulation of the S2 ventral and dorsal roots together resulted in the expulsion of only one or two marbles (Figure 6). This difference suggests that stimulating the sensory nerves of the dorsal root may have elicited an additional reflex to the anal sphincter, which may have caused defecation dysfunction and prevented the rectum from emptying completely. This possibility was clearly demonstrated in cat #1, in which the expulsion of the third marble was incomplete because the contraction of the anal sphincter fixed the marble in place (Figure 6, panel A). If the clitoral nerve had been blocked in this experiment, the external anal sphincter would have relaxed and the third marble would have been expelled completely. However, if the defecation dysfunction was due to contraction of the internal anal sphincter (smooth muscle) rather than the external anal sphincter (striate muscle), then the clitoral nerve blockade would have been ineffective. In this study, we inserted marbles into the rectum to examine defecation, so we did not record the internal anal sphincter and rectal contraction pressures. A small, movable balloon is required in the distal intestine to expel the balloon and simultaneously measure pressure during defecation. Therefore, further studies are needed to better understand the coordination of the rectum and anal sphincter during defecation induced by sacral stimulation.

[0092] In the present study, colonic contractions and defecation induced by S2 root stimulation always required a higher stimulation intensity than that eliciting hindlimb and / or tail movements. This result is expected because in cats, the afferent and efferent fibers of the S2 spinal root innervating the colon are unmyelinated small C fibers, which have a higher excitation threshold than the large motor fibers. Since the small C fibers of the dorsal root are also involved in nociceptive transmission, the stimulation intensity required for defecation may also produce pain sensations at the same time. In patients with complete SCI, this should not be a significant issue for restoring defecation function, since there is no sensation below the level of injury. However, if the extrinsic innervation of the human large intestine is similar to that of cats, it would be problematic to induce defecation in non-SCI individuals with chronic constipation.

[0093] Recent applications of sacral neuromodulation to treat non-SCI patients with chronic constipation have not yielded conclusive clinical results, which may in part be due to the use of a low stimulation intensity that only results in somatosensation. This low stimulation intensity probably does not directly stimulate the nerve fibers of the sacral root that innervate the large intestine. However, it may indirectly regulate large intestinal function by activating the large somatosensory fibers of the sacral root that may trigger central mechanisms to promote colonic motility. Although this central regulatory mechanism may be sensitive to stimulation frequency, recent clinical trials have used only a single stimulation frequency of 14 Hz to treat non-SCI patients with chronic constipation. Our study indicates that a lower frequency of 7 Hz is optimal for sacral root stimulation to induce colonic contractions, whereas other studies in rats and dogs have acknowledged that effective frequencies are 5 Hz or 10 Hz. It therefore appears that frequencies lower than 14 Hz should be tested in clinical studies to treat non-SCI patients with chronic constipation.

[0094] Our study also shows that continuous stimulation can cause fatigue of colonic contractions, whereas intermittent stimulation is more fatigue-resistant (Figure 5). This indicates that continuous stimulation of the sacral roots used in recent clinical trials to treat chronic constipation may not be optimal, and that intermittent stimulation may be more effective in regulating colonic motility to improve colonic transit time. Recent animal studies have begun to focus on developing optimal stimulation parameters to promote colonic motility and improve sacral neuromodulation therapy for non-SCI patients with chronic constipation.

[0095] In summary, this study in cats optimized stimulation parameters for sacral root stimulation to induce colonic contractions and defecation. The results have important implications for the design of novel neuromodulation devices to restore defecation function after SCI and for optimizing sacral neuromodulation parameters to treat non-SCI patients with chronic constipation.

[0096] Example 2 The experimental protocol and animal use in this study were approved by the University of Pittsburgh Institutional Animal Care and Use Committee.

[0097] material and method A total of eight male cats (4.6 ± 0.2 kg; domestic shorthair) were anesthetized with isoflurane (2–5% in oxygen) during surgery and then switched to α-chloralose anesthesia (65 mg / kg iv initially, supplemented as needed) during data collection. A catheter was placed in the left cephalic vein for fluid infusion. A tracheotomy was performed and intubation was performed to secure the airway. A catheter was placed in the right carotid artery to monitor systemic blood pressure with a pressure transducer (BLPR2 WPI, Sarasota, FL) connected to an amplifier (TBM4M, WPI, Sarasota, FL). Heart rate and blood oxygen were monitored with a tongue-mounted pulse oximeter (9847V; NONIN Medical, Plymouth, MN). An abdominal incision was made and a catheter was inserted into the bladder via the urethra to drain the bladder during testing, and the urethra was ligated with sutures. The abdominal incision was then closed with sutures.

[0098] The spinal cord was exposed from lumbar L7 to sacral S3 by dorsal laminectomy. The dura was opened and each rootlet from S1 to S3 was identified. The dorsal and ventral roots were separated and either the ventral root was stimulated individually or both the dorsal and ventral roots were stimulated together (Figure 7). During the experiment, the animal was in a prone position and the spinal incision was kept open with a surgical retractor, forming a pool filled with warm (35-37 °C) mineral oil. The animal's body temperature was maintained at 35 °C to 37 °C using a heating pad. Stimulation was delivered to each sacral rootlet by slightly lifting the spinal root above the spinal cord using a stainless steel bipolar hook electrode (electrode spacing 2-3 mm). Stimulation was generated with a stimulator (S88, Grass Instruments, West Warwick, RI) and delivered via a constant voltage stimulation isolator (SIU5A, Grass Instruments, West Warwick, RI).

[0099] At the beginning of the experiment, stimulation (frequency 30 Hz, pulse width 0.2 ms, duration 1–2 min) was applied at minimum intensity (0.5 V) to the sacral S1 ventral root via a hook electrode. If erection was not observed, the stimulation intensity was increased and then the test was repeated again until penile erection was observed. If S1 ventral root stimulation was ineffective, the stimulation electrode was moved to the S2 ventral root and the test was repeated. Penile erection, evident as full protrusion of the penis and rigidity to bending, was always observed by stimulation of individual S1 and S2 ventral roots. After penile erection was observed, a 20-gauge catheter was inserted into the corpus cavernosum through a small incision at the tip of the penis to record penile pressure during erection via a pressure transducer (BLPR2 WPI, Sarasota, FL) connected to an amplifier (TBM4M, WPI, Sarasota, FL) (Figure 7). Pressure data were recorded on a chart recorder (TA4000, Gould, Chandler, AZ) and digitized by a computer running the LabView program (National Instruments, Austin, TX). Because electrically induced penile protrusion correlates very well with increases in cavernosal pressure, pressure recordings were used in this study as a quantitative measure of penile erection.

[0100] After placement of the penile catheter (N = 8 cats), stimulation (frequency 30 or 40 Hz, pulse width 0.2 ms, duration 1 min) was applied via hook electrodes to individual sacral ventral roots (S1, S2, or S3) on the left and right sides at a range of intensities (0.5–15 V) to determine the intensity threshold (T) for eliciting an observable increase in penile pressure. Penile responses to different stimulation frequencies (5–80 Hz) were then tested using intensities (1.5–3 T) that elicited maximum penile pressure (>100 cmH2O). If stimulation to individual ventral roots did not elicit penile pressures exceeding 100 cmH2O, frequency responses were examined using the maximum stimulation intensity that did not produce movement of the animal's lower body. It was intended not to immobilize the hip joints and lower spine because sacral root stimulation with hook electrodes could produce localized movements of the tail or hind limbs. However, the maximum stimulation intensity was limited by movements of the lower spine that would displace the hook electrode from the nerve. After each ventral root was examined, the ventral root (S1 or S2) that induced the greatest penile pressure was combined with the dorsal root, and the combination was continuously stimulated for 10 min at the most effective frequency (30 Hz) and intensity to determine whether the induced penile erection was sustainable for the entire stimulation period. Finally, the spinal cord was completely cut at the T9-T10 level (N = 6 cats). Approximately 10 min after spinal cord section, the same spinal root (ventral and dorsal roots combined) was repeatedly stimulated for 10 min to induce penile erection. No drugs were used to treat blood pressure changes caused by spinal cord section.

[0101] To compare penile erectile responses induced by stimulating different ventral roots at different frequencies, the maximum amplitude of the stimulation-induced penile pressure was measured and averaged among different animals for the same stimulation condition. To determine the durability of the induced penile erection, the maximum penile pressure induced by 10 min of continuous stimulation was compared with the pressure at the end of the 10 min of stimulation. To examine the effect of spinal cord section, the maximum penile pressure induced by 10 min of continuous stimulation was compared before and after spinal cord section. Data from different animals were averaged and presented as mean ± SE. For statistical analysis using a software package (Prism 9.3.1, GraphPad Software, San Diego, CA), paired t-tests or repeated measures Friedman test followed by Dunnett's multiple comparisons were performed. Statistical significance was defined as p < 0.05.

[0102] result Penile erection was observed as full protrusion of the penis accompanied by rigidity by stimulation of the S1 ventral root in six cats (S2 and S3 ineffective) and by stimulation of the S2 ventral root in two cats (S1 and S3 ineffective). Stimulation parameters were frequency 30 Hz, pulse width 0.2 ms, and intensity 4.3 ± 1.0 V (0.5-8 V). These responses, quantified by penile pressure recordings, showed that S1 or S2 ventral root stimulation induced a large increase in penile pressure from a baseline pressure of 25 ± 1 cmH2O to 177 ± 14 cmH2O (S1) or 147 ± 2 cmH2O (S2) in six and two cats, respectively (Figure 8, Panel C). The optimal stimulation frequency for inducing penile erection by S1 or S2 ventral root stimulation was 30-40 Hz (Fig. 8, panel D), but lower (10-20 Hz, Fig. 8, panel A) or higher (60-80 Hz, Fig. 8, panels A and B) frequencies were also able to induce large increases in penile pressure in some cats. The stimulation intensity for 30-40 Hz S1 or S2 ventral root stimulation inducing the maximum increase in penile pressure was 3.5 ± 1.4 V (0.6-12 V), which was always above the motor threshold for inducing leg muscle contraction (S1) or anal sphincter contraction (S2).

[0103] Continuous stimulation (30 Hz) of the S1 or S2 spinal roots (i.e., the ventral and dorsal roots combined) for 10 min induced a large increase in penile pressure (190 ± 8 cmH2O) (Figure 9). The maximum penile pressure either persisted (Figure 9, Panel A) or developed gradually (Figure 9, Panel B) during the 10 min of stimulation. The penile pressure at the end of the 10 min of stimulation was not significantly different from the maximum pressure developed during the stimulation (Figure 9, Panel C). The maximum penile pressure induced by stimulating the ventral and dorsal roots together was also not significantly different from the maximum pressure induced by stimulation of the ventral root alone (Figure 8, Panel D and Figure 9, Panel C).

[0104] After complete transection of the spinal cord at the T9-T10 level, continuous stimulation (30 Hz) of the S1 or S2 spinal roots (ventral and dorsal roots combined) for 10 min also evoked a large increase in penile pressure (186 ± 9 cmH2O) (Figure 10). As seen before spinal cord transection, the maximum penile pressure also persisted or developed gradually during the 10 min stimulation (Figure 10, Panel B). However, the evoked penile pressure was significantly (p = 0.0025) reduced to 113 ± 19 cmH2O after spinal cord transection compared to the penile response before spinal cord transection (186 ± 9 cmH2O) (Figure 10, Panel C). Blood pressure was also significantly (p = 0.0027, N = 6) reduced from 229 ± 11 cmH2O to 186 ± 7 cmH2O by spinal cord transection, but was unchanged by sacral root stimulation.

[0105] Consideration This study in anesthetized cats demonstrated that penile erections induced by sacral root stimulation depended on the stimulation frequency and the spinal segment stimulated. In each animal, one spinal root, most commonly S1, which contains a small portion of the parasympathetic efferent projections to the pelvic viscera in cats, elicited the most prominent response. The maximum increase in penile pressure occurred with 30–40 Hz stimulation (Figure 8) and was sustained even with prolonged (10 min) stimulation (Figure 9), and persisted after acute complete transection of the spinal cord (Figure 10). These data suggest that the efficacy of sacral neuromodulation in improving penile erectile function in spinal cord injured individuals depends on the selection of the appropriate spinal root and the optimal stimulation frequency.

[0106] Previous studies have shown that electrical stimulation of the pelvic nerve, cavernous nerve, or dorsal penile nerve can induce penile erection in mice, rats, cats, dogs, monkeys, or humans. However, the pelvic and cavernous nerves require invasive surgery to implant stimulating electrodes, and the dorsal penile nerve is not a convenient location to place a stimulating electrode during sexual intercourse. Therefore, these stimulation methods have not been widely applied clinically to treat erectile dysfunction. Sacral ventral root stimulation was also shown to be effective in inducing penile erection in this study and in previous studies in cats and dogs. In addition, sacral ventral root stimulation was used to restore bladder and erectile function in some SCI patients. However, invasive spinal surgery is required to implant stimulating electrodes in the sacral ventral root, and this effective treatment cannot be used solely to treat erectile dysfunction in SCI or non-SCI patients. This study in cats shows that stimulation of the sacral root can induce penile erection. Previous studies in dogs have shown similar effects. The significance of sacral root stimulation instead of the ventral root is the possibility of adopting a minimally invasive surgical approach for stimulation. Human sacral roots can be accessed by percutaneously inserting a needle to place a stimulation lead electrode. This surgical approach is commonly used in sacral neuromodulation therapy for overactive bladder. Therefore, this study has important implications for developing new sacral neuromodulation therapy using a minimally invasive surgical approach to restore erectile function in both SCI and non-SCI patients.

[0107] Previous studies using sacral neuromodulation therapy to treat overactive bladder have also evaluated its effect on penile erection in both SCI and non-SCI patients. Subjects with moderate to mild erectile dysfunction reported a significant improvement in the quality of their sexual life with sacral neuromodulation therapy, according to questionnaires. However, these studies used stimulation parameters optimized for the treatment of overactive bladder, i.e., a stimulation frequency of 20 Hz at sensory threshold intensity. These stimulation parameters may not be optimal for the treatment of erectile dysfunction, as the study showed that a higher stimulation frequency (30–40 Hz) at an intensity above the sensory and motor thresholds could rapidly induce penile erection at the time stimulation was turned on and could be sustained throughout the entire 10-minute stimulation. This type of on-demand erection should be much more satisfying for patients than the improvement in quality of life provided by continuous (24 h × 7 days) sacral neuromodulation at a lower frequency and weaker stimulation intensity. Therefore, it seems likely that higher frequencies (30-40 Hz) and stronger stimulation intensities (above sensory and motor thresholds) should be tested in clinical studies to treat erectile dysfunction. Although stronger stimulation induces leg movements, the contraction of the leg muscles is tonic and movements occur only early in the stimulation, which should not interfere with successful intercourse. When anterior root stimulation was used to induce penile erection in SCI patients, leg movements were also induced but did not interfere with successful intercourse.

[0108] Stimulation of the sacral root (ventral and dorsal roots combined) induced a large increase in penile pressure similar to that produced by stimulation of the ventral root alone (Figure 8). This result indicates that activating additional sensory nerves in the dorsal root did not prevent penile erection induced by directly stimulating the efferent nerves of the ventral root. Previous studies in dogs have also reported no difference in penile erection induced by stimulation of the ventral root alone or by stimulating the ventral and dorsal roots together. In this study, the threshold intensity for eliciting leg movements or anal sphincter contraction was not measured, making it difficult to estimate which type of nerve fibers were activated in the sacral root when penile erection was induced. In human applications under awake conditions, activation of sensory nerves may cause discomfort or pain, which may limit stimulation intensity and therefore the effectiveness of stimulation in treating erectile dysfunction. This potential issue can only be resolved by clinical studies in non-SCI human subjects. However, this should not be a problem for subjects with complete SCI who have no sensation below the injury.

[0109] This study shows that penile erections induced by sacral root stimulation were sustained or developed gradually during the 10 min stimulation (Figure 9, panels A-B). This indicates that longer durations of sacral root stimulation could result in longer-lasting erections. This also indicates that stimulation of dorsal root afferents did not reflexively activate inhibitory sympathetic pathways that could inhibit penile erection. Stimulation of the sacral root likely activated both parasympathetic and somatic sympathetic pathways, producing erection and penile rigidity. However, after spinal cord transection, the amplitude of induced penile pressure was significantly reduced, possibly due to the spinal shock effect and the reduction in blood pressure after acute spinal cord transection. Nevertheless, sacral root stimulation induced a large (>100 cmH2O, Figure 10) sustained increase in penile pressure even after acute spinal cord transection, indicating that this stimulation may be useful for erectile function recovery after SCI. Whether sacral root stimulation is less effective in inducing penile erection in SCI patients than in non-SCI patients remains a question to be answered by human clinical studies. However, it is known that sacral anterior root stimulation is effective in inducing penile erection of sufficient strength for sexual intercourse in SCI patients. In summary, in this study in cats, we optimized the stimulation parameters of sacral root stimulation to induce penile erection. The results have important implications for the design of new neuromodulation devices to restore erectile function after SCI or for optimizing sacral neuromodulation parameters to treat non-SCI patients with erectile dysfunction.

[0110] Although the invention has been described with reference to the above detailed description, those skilled in the art will appreciate that modifications may be made within the spirit of the invention. Accordingly, the above should not be taken as limiting, and the scope of the invention is defined by the appended claims.

Claims

Claim 1 A system for inducing colonic contractions and / or defecation in a patient, comprising: at least one lead configured to be disposed proximate to one or more sacral roots of the patient's spinal cord and / or one or more sacral segments of the patient's spinal cord; a pulse generator in electrical communication with the at least one lead; and at least one processor in communication with the pulse generator, the processor being programmed or configured to cause the pulse generator to deliver one or more electrical pulses at a frequency of about 3 Hz to about 10 Hz via the at least one lead. Claim 2 The system of claim 1, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses at a frequency of about 7 Hz via the at least one lead. Claim 3 The system of claim 1, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead at an intensity capable of inducing colonic / rectal contractions in the range of about 0.1 V to about 20 V and / or about 0.1 mA to about 20 mA. Claim 4 The system of claim 1, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead at an intensity of about 1 V and / or 1 mA. Claim 5 The system of claim 1, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead at an intensity of about 4 V and / or 4 mA. Claim 6 The system of claim 1, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead at an intensity of about 6 V and / or 6 mA. Claim 7 The system of claim 1, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead continuously or intermittently. Claim 8 The system according to claim 7, wherein the processor programs or configures the pulse generator to deliver one or more electrical pulses via the at least one lead for about one minute and then to not apply stimulation for about one minute.

9. A system for inducing penile erection in a patient, comprising: at least one lead configured to be disposed proximate to one or more sacral roots of the patient's spinal cord and / or one or more sacral segments of the patient's spinal cord; a pulse generator in electrical communication with the at least one lead; and at least one processor in communication with the pulse generator, the processor being programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead at a frequency of from about 10 Hz to about 80 Hz.

10. The system according to claim 9, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead at a frequency of from about 30 Hz to about 40 Hz.

11. The system according to claim 9, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead at an intensity capable of inducing penile erection in the range of from about 0.1 V to about 20 V and / or from about 0.1 mA to about 20 mA.

12. The system according to claim 9, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead at an intensity of about 3 V and / or 3 mA.

13. The system according to claim 9, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead at an intensity of about 6 V and / or 6 mA.

14. The system according to claim 9, wherein the processor is programmed or configured to cause the pulse generator to deliver one or more electrical pulses via the at least one lead continuously or intermittently.

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