Patent Application
20240424299
Provided herein is a method of stimulating the sacral spinal cord/roots and related devices, more specifically a method of modulating bowel and sexual function by stimulating the sacral spinal cord/roots, and devices for carrying out such methods.
A number of conditions arise from disruption of normal physiological processes in the lower pelvis. Conditions, such as urinary incontinence, overactive bladder, urine retention and voiding dysfunction, detrusor sphincter dyssinergia, fecal incontinence, constipation, irritable bowel syndrome, sexual dysfunction in both men and women, premature ejaculation, decreased sexual sensation, anorgasmia, urethral pain, prostate pain, vulvodynia, anal pain, rectal pain, and bladder pain are among those conditions. Those conditions can result from neurological impairment or from other diseases or conditions, for example spinal cord injury or stroke, trauma, disease (e.g., multiple sclerosis), and/or congenital defects.
In the past, such conditions have been treated by sacral anterior root stimulation, which requires a major invasive spinal surgery to expose the sacral spinal roots for implantation of stimulation electrodes. Sacral posterior rhizotomy prevents the dyssynergic contraction of anal sphincter, but it also eliminates spinal reflex defecation and sexual function such as penile erection. Therefore, a need exists for a minimally invasive neuromodulatory approach that does not require invasive spinal surgery and sacral posterior rhizotomy.
Provided herein is a method of inducing colon contractions and/or defecation in a patient, including 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 from about 3 Hz to about 10 Hz.
Also provided herein is a method of inducing a 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 from about 10 Hz to about 80 Hz.
Further non-limiting embodiments are set forth in the following clauses:
Clause 1. A method of inducing colon 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 from about 3 Hz to about 10 Hz.
Clause 2. The method of clause 1, wherein the one or more sacral roots or sacral cord segments are one or more of the patient's S1, S2, S3, S4, and/or S5 sacral roots or sacral cord segments.
Clause 3. The method of clause 1 or 2, wherein the patient is human.
Clause 4. The method of any of clauses 1-3, wherein the one or more sacral roots or sacral cord segments of the patient's spinal cord innervate the patient's colon and rectum.
Clause 5. The method of any of clauses 1-4, wherein the stimulation is applied to the ventral/anterior and/or dorsal/posterior sacral roots.
Clause 6. The method of any of clauses 1-5, wherein the stimulation is applied to the patient's S2 and/or S3 sacral roots and/or sacral cord segments.
Clause 7. The method of clause 6, wherein the stimulation is applied to the patient's S2 and/or S3 ventral/anterior root.
Clause 8. The method of any of clauses 1-7, wherein the stimulation is applied at a frequency of about 7 Hz.
Clause 9. The method of any of clauses 1-8, wherein the stimulation is applied at an intensity that can induce colon/rectum contraction ranging about 0.1V to about 20 V and/or about 0.1 mA to about 20 mA.
Clause 10. The method of clause 9, wherein the stimulation is applied at an intensity of about 1 V and/or 1 mA.
Clause 11. The method of clause 9, wherein the stimulation is applied at an intensity of about 4 V and/or 4 mA.
Clause 12. The method of clause 9, wherein the stimulation is applied at an intensity of about 6 V and/or 6 mA.
Clause 13. The method of any of clauses 1-12, wherein the stimulation is applied continuously or intermittently.
Clause 14. The method of clause 13, wherein the intermittent stimulation is applied for about 1 minute followed by about 1 minute where no stimulation is applied.
Clause 15. A method of inducing a 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 from about 10 Hz to about 80 Hz.
Clause 16. The method of clause 15, wherein the one or more sacral roots or sacral cord segments are one or more of the S1, S2, S3, S4, and/or S5 sacral roots or sacral cord segments.
Clause 17. The method of clause 15, wherein the patient is human.
Clause 18. The method of any of clauses 15-17, wherein the one or more sacral roots or sacral cord segments of the patient's spinal cord innervate the patient's penis.
Clause 19. The method of any of clauses 15-18, wherein the stimulation is applied to the ventral/anterior and/or dorsal/posterior sacral roots.
Clause 20. The method of any of clauses 15-19, wherein the stimulation is applied to the S1 and/or S2 sacral roots and/or sacral cord segments.
Clause 21. The method of clause 20, wherein the stimulation is applied to the S1 and/or S2 ventral/anterior root.
Clause 22. The method of any of clauses 15-21, wherein the stimulation is applied at a frequency of about 30 Hz to about 40 Hz.
Clause 23. The method of any of clauses 15-22, wherein the stimulation is applied at an intensity that can induce penile erection ranging about 0.1 V to about 20 V and/or about 0.1 mA to about 20 mA.
Clause 24. The method of clause 23, wherein the stimulation is applied at an intensity of about 3 V and/or 3 mA.
Clause 25. The method of clause 23, wherein the stimulation is applied at an intensity of about 6 V and/or 6 mA.
Clause 26. The method of any of clauses 15-25, wherein the stimulation is applied continuously or intermittently.
Clause 27. The method of any of clauses 15-26, wherein the stimulation causes an increase in pressure in the patient's corpus cavernosum of at least 50 cm H2O.
Clause 28. The method of any of clauses 15-27, wherein the stimulation causes an increase in pressure in the patient's corpus cavernosum of at least 100 cm H2O.
Clause 29. A system for inducing colon contractions and/or defecation in a patient, comprising: at least one lead configured to be placed in proximity 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, 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 from about 3 Hz to about 10 Hz.
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.
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 that can induce colon/rectum contraction ranging about 0.1V to about 20 V and/or about 0.1 mA to about 20 mA.
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 through the at least one lead at an intensity of about 1 V and/or 1 mA.
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 through the at least one lead at an intensity of about 4 V and/or 4 mA.
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 through the at least one lead at an intensity of about 6 V and/or 6 mA.
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 through the at least one lead continuously or intermittently.
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 through the at least one lead for about 1 minute followed by about 1 minute where no stimulation is applied.
Clause 37. A system for inducing a penile erection in a patient, comprising: at least one lead configured to be placed in proximity 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, 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 from about 10 Hz to about 80 Hz.
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.
Clause 39. The system of clause 37 or 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 that can induce penile erection ranging about 0.1 V to about 20 V and/or about 0.1 mA to about 20 mA.
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 through the at least one lead at an intensity of about 3 V and/or 3 mA.
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 through the at least one lead at an intensity of about 6 V and/or 6 mA.
Clause 42. The system of any of clauses 37-41, wherein the processor is programmed or configured to cause the pulse generator to cause the pulse generator to deliver one or more electrical pulses through the at least one lead continuously or intermittently.
The use of numerical values in the various ranges specified in this application, unless expressly indicated otherwise, are stated as approximations as though the minimum and maximum values within the stated ranges are both preceded by the word “about”. In this manner, slight variations above and below the stated ranges can be used to achieve substantially the same results as values within the ranges. Also, unless indicated otherwise, the disclosure of these ranges is intended as a continuous range including every value between the minimum and maximum values. For definitions provided herein, those definitions refer to word forms, cognates, and grammatical variants of those words or phrases.
The figures accompanying this application are representative in nature, and should not be construed as implying any particular scale or directionality, unless otherwise indicated. For purposes of the description hereinafter, the terms “upper”, “lower”, “right”, “left”, “vertical”, “horizontal”, “top”, “bottom”, “lateral”, “longitudinal” and derivatives thereof shall relate to the invention as it is oriented in the drawing figures. However, it is to be understood that the invention may assume various alternative variations and step sequences, except where expressly specified to the contrary. Hence, specific dimensions and other physical characteristics related to the embodiments disclosed herein are not to be considered as limiting.
As used herein, the term “comprising” and like terms are open-ended. The term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. The term “consisting of” excludes any element, step, or ingredient not specified in the claim.
As used herein, the terms “a” and “an” refer to one or more.
As used herein, the term “patient” is any mammal, including humans, and a “human patient” is any human
As used herein, the terms “communication” and “communicate” refer to the receipt, transmission, or transfer of one or more signals, messages, commands, or other type of data. For one unit or device to be in communication with another unit or device means that the one unit or device is able to receive data from and/or transmit data to the other unit or device. A communication can use a direct or indirect connection, and can be wired and/or wireless in nature. Additionally, two units or devices can be in communication with each other even though the data transmitted can be modified, processed, routed, etc., between the first and second unit or device. For example, a first unit can be in communication with a second unit even though 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 one unit and transmits processed data to the second unit. It will be appreciated that numerous other arrangements are possible. Any known electronic communication protocols and or algorithms can 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 transmissions, Global System for Mobile Communications (GSM), 3G/4G/LTE, BLUETOOTH, ZigBee, EnOcean, TransferJet, Wireless USB, and the like known to those of skill in the art.
As used herein, “electrical communication,” for example in the context of transmitting electrical pulses from a pulse generator to an electrode refers to sending an electrical pulse produced by a pulse generator to a skin surface electrode, an electrode lead, a magnetic coil, or like devices capable of generating electrical current to stimulate a nerve or neuron as described herein, typically through an electrically-conductive lead, such as a wire.
As used herein, the “intensity threshold” (T) means the minimal intensity that can induce a desired physiological response such as colon/rectum contraction, defecation, or penile erection and/or the minimal intensity that can induce a contraction in the proximal portion of the colon, and/or an increase in pressure in the colon or the corpus cavernosum.
The “intensity” of an electrical pulse is proportional to, and refers to the voltage (V) and/or current (e.g., milliAmperes or mA) applied to the nerve or neuron, with an increased intensity being proportional to an increased voltage or an increased current applied to the nerve or neuron. Those of skill will appreciate that, assuming electrode-tissue resistance of 1 kOhm, 1 V is approximately equal to 1 mV in terms of intensity.
U.S. Pat. No. 8,805,510 is incorporated by reference herein in its entirety.
Provided herein are methods, and devices/systems useful in carrying out such methods, of stimulating the sacral spinal cord/roots of a patient to elicit a physiological response, in particular colon/rectum contraction and/or defecation. Also provided herein are methods, and devices/systems useful in carrying out such methods, of stimulating the sacral spinal cord/roots of a patient to elicit a physiological response, in particular a penile erection. Useful stimulation can be electrical, through an implanted pulse generator, or non-invasive, through transcutaneous methods, such as transcutaneous electrical stimulation. Useful stimulation may also be non-invasive, through a magnetic stimulator that can be placed near or applied to an outer surface of the body to induce electrical current in the body to stimulate the spinal roots/cord, for example by using a conductive coil outside the body to generate a magnetic field for inducing an electrical current at the target(s) of interest. The methods and devices/systems disclosed herein are superior to other methods/systems, for example stimulation of the ventral root (e.g., in animals), at least because such other methods require a more invasive electrode placement.
The electrical stimulation described herein can include electrical pulses that can have any suitable characteristic, so long as the stimulation is effective to achieve the desired physiological response. As such, the terms “electrical stimulation” and “electrical pulses” are used interchangeably herein. As will be recognized by a person of skill in the art, characteristics of the electrical pulses, including, without limitation, amplitude (pulse strength, referring to the magnitude or size of a signal voltage or current), voltage, amperage, duration (e.g., pulsewidth), frequency, polarity, phase, relative timing, and symmetry of positive and negative pulses in biphasic stimulation, and/or wave shape (e.g., square, sine, triangle, sawtooth, or variations or combinations thereof) may be varied in order to provide the desired physiological response. So long as other characteristics of the electrical signals (e.g., without limitation, amplitude, voltage, amperage, duration, polarity, phase, relative timing and symmetry of positive and negative pulses in biphasic stimulation, and/or wave shape) are within useful ranges, modulation of the pulse frequency will achieve the desired physiological response.
One characteristic of the electrical signals used to produce a desired response, as described above, is the frequency of the electrical pulse. Although effective ranges (e.g., frequencies able to produce a stated effect) may vary from subject-to-subject, and the controlling factor is achieving a desired outcome, certain, non-limiting exemplary ranges may be as follows. In non-limiting embodiments, where the desired physiological response is defecation (e.g., colon 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-10 Hz, about 5 Hz to about 10 Hz, about 7 Hz-10 Hz, about 5 Hz, about 7 Hz, or any subrange or value therebetween. In non-limiting embodiments, where the desired physiological response is a penile erection, useful frequencies range from 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, all values and subranges therebetween inclusive. In non-limiting embodiments, the electrical pulses are delivered with a pulse width of about 0.2 ms.
As indicated above, a characteristic of electrical pulses is their intensity which in a medium of stable or relatively stable resistance, such as mammalian tissue, can be characterized as relating to current (I, typically measured in mA), or voltage (V, typically measured in mV or V), based on Ohm's Law. It should, therefore, be understood that the intensity of the stimulation is a matter of both V and I, and as such, both are increased, e.g., proportionally or substantially proportionally, with increased intensity of stimulation. As such, one characteristic of the pulses is the current that is applied to produce a physiological response. Stimulation can be achieved in a typical range of from 0.01 mA to 20 mA and/or 0.1 V to 20 V, all subranges and values therebetween inclusive.
Another characteristic of the intensity of the pulses is voltage. Stimulation can be achieved in a typical range of from 1 mV to 20 V, all subranges and values therebetween inclusive. In non-limiting embodiments or aspects, the stimulation is delivered with electrical pulses having a voltage of from 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 4V, about 6 V, or any subrange or value therebetween.
As discussed above, the intensity threshold (T) of the electrical pulses delivered during stimulation can be defined as the minimal intensity that can induce a desired physiological response such as colon/rectum contraction, defecation, or penile erection and/or the minimal intensity that can induce a contraction in the proximal portion of the colon, and/or an increase in pressure in the colon or the corpus cavernosum. Useful ranges in terms of the intensity of the electrical pulses that can be delivered, relative to the threshold, can include about IT to about 4T, about 1.5T to about 3T, about IT, about 1.5T, about 3T, about 4T, or any subrange or value therebetween. In non-limiting embodiments, the intensity of the electrical pulses is 1.5T or 2T or 2.5 T or 3T.
As indicated above, the waveform of the pulses may vary, so long as the desired physiological response is realized. One skilled in the art will appreciate that other types of electrical stimulation may also be used in accordance with the present invention. Monophasic or biphasic stimuli, or a mixture thereof, may be used. Damage to nerves by the application of an electrical current may be minimized, as is known in the art, by application of biphasic pulses or biphasic waveforms to the nerve(s), as opposed to monophasic pulses or waveforms that can damage nerves in some instances of long-term use. “Biphasic current,” “biphasic pulses,” or “biphasic waveforms” refer to two or more pulses that are of opposite polarity that may be of equal or substantially equal net charge (hence, biphasic and charge balanced), and may be symmetrical, asymmetrical, or substantially symmetrical. This is accomplished, for example, by applying through an electrode one or more positive pulses, 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 electrode is zero, or approximately zero. For charge-balanced biphasic stimulation, the opposite polarity pulses may have different amplitudes, profiles, or durations, so long as the net applied charge by the biphasic pulse pair (the combination of the positive and negative pulses) is approximately zero.
The waveform may be of any useful shape, including without limitation: sine, square, rectangular, triangular, sawtooth, rectilinear, pulse, exponential, truncated exponential, or damped sinusoidal. The pulses may increase or decrease over the stimulation period. In aspects, the waveform is rectangular. The pulses may be applied continuously or intermittently as needed. For example, the stimulation may be applied for short intervals (e.g., 1-10 minutes) or longer intervals (360 minutes or even longer, for example days, weeks, months, or even years) to achieve longer-lasting physiological responses, in terms of hours, days, weeks, months, or years. In aspects, 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 5 minutes of total stimulation is delivered. In non-limiting embodiments, intermittent stimulation is followed a period of continuous stimulation. In non-limiting embodiments or aspects, the stimulation is delivered only when the physiological response is desired.
As described above, the stimulation may be applied intermittently (that is, the pulses are turned on and off alternately during a stimulation interval for any time period) during continuous or interval stimulation protocols. For example, the stimulation may be applied for 5 seconds on and 5 seconds off over an interval of, for example, 1-10 minutes or longer (e.g., hours, days, weeks, months, years). Other examples of intermittent application of pulses may be 1-90 seconds on and 1-90 seconds off over up to a 360 minute time period. For example, intermittent application of pulses may be continuous, that is, for as long as the pulses are having the desired effect, and for as long as the patient desires (i.e., is not painful or harmful to the patient). In one aspect, the stimulation is provided continuously, for example, to treat severe symptoms, or any symptom that does not respond to intermittent, short-term stimulation to the degree desired by a clinician or the patient.
Stimulation as described herein can be applied to the sacral roots of a patient's spinal cord and/or sacral spinal cord to produce a desired physiological response. In non-limiting embodiments, the desired physiological response is colon/rectum contraction and/or defecation. In non-limiting embodiments, the desired physiological response is a penile erection. In non-limiting embodiments or aspects, the patient has a spinal cord injury, or is suffering from a condition, such as constipation, optionally chronic constipation. Without wishing to be bound by the theory, constipation, such as chronic constipation, is relieved by the methods described herein by stimulating contraction of the colon/rectum. In non-limiting embodiments or aspects, the S1, S2, S3, S4, and/or S5 sacral roots and/or cords are stimulated with pulses having parameters as described herein. Those of skill in the art will appreciate that the specific sacral root(s) and/or sacral spinal cord segments that are stimulated will depend on the physiological response that is desired, as well as the identity of the patient, specifically the species of the patient. For example, in the Examples provided below, cats are used as experimental subjects, and those of skill appreciate that the feline sacral roots may differ from those of a human. See, e.g., 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 produced in a cat by stimulating the S1, S2, and/or S3 ventral root, dorsal root, or both, those of skill will appreciate that the human equivalent will be identified by different terminology (e.g., anterior root, posterior root, or both), and may involve stimulation of different roots, as the human spinal cord includes S4 and S5 sacral roots, where the feline spinal cord does not. Moreover, the S1 root of the cat may correspond to a different root in a human. Those of skill will appreciate that the key is targeting one or more sacral roots that innervate the target tissue/organ of interest (e.g., the colon or the penis).
In non-limiting embodiments the desired physiological response is defecation (e.g., colon contraction), the patient is a human, and the S1, S2, S3, S4, and/or S5 anterior roots are stimulated. In non-limiting embodiments, only the S2 root is stimulated, optionally both the ventral/anterior and dorsal/posterior roots, optionally only the ventral/anterior S2 root. In non-limiting embodiments, the patient is a human and the S1-S3 ventral/anterior and dorsal/posterior roots are stimulated.
In non-limiting embodiments the desired physiological response is a penile erection, the patient is a 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 and dorsal/posterior roots, optionally only the ventral/anterior S2 root. In non-limiting embodiments, the patient is a human and the S1 and S2 roots are stimulated, optionally both the ventral/anterior and dorsal/posterior roots In non-limiting embodiments, the patient is a human and the S1-S3 ventral/anterior and dorsal/posterior roots are stimulated. In non-limiting embodiments, the physiological outcome is measured by an increase in pressure, or as an obtained pressure, within the corpus cavernosum of the penis. In non-limiting embodiments or aspects, the stimulation causes increase of at least 25, at least 50, at least 100, at least 125, and/or at least 150 cm H2O within the patient's corpus cavernosum, all values and subranges therebetween inclusive. In non-limiting embodiments or aspects, the stimulation causes pressure within the patient's corpus cavernosum to reach at least 100, at least 125, and/or at least 150 cm H2O, all values and subranges therebetween inclusive.
Turning to the figures, also provided herein are devices for applying stimulation with parameters as described herein, in a manner sufficient to induce the desired physiological response.
The devices of
Referring to
In some examples, the controller includes a program, code, a set of instructions, or some combination thereof, executable by the processor for independently or collectively instructing the device to interact and operate as programmed, referred to herein as “programming instructions”. In some examples, the controller is configured to issue instructions to the power supply/pulse generator to initiate electrical pulses, and to control output parameters of the power supply in a manner sufficient to stimulate the sacral spinal cord/roots. Those of skill in the art will appreciate that a processor associated with a device 10, 110 disclosed herein can be programmed to deliver stimulation as described generally throughout this disclosure. In any case, the controller is configured to receive and process electrical pulse parameters, either programmed into the device or from an external source, and optionally to output data obtained from the power supply as feedback to determine if the power supply is producing a desired output. Processing can include applying filters and other techniques for removing signal artifacts, noise, baseline waveforms, or other items from captured signals to improve readability.
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 to provide a desired physiological response as described herein. These parameters are described above, but can include stimulation at from 1 Hz to 80 Hz, at an intensity of 0.01 mA to 20 mA and/or from 0.01 V to 20 V, for a duration of seconds to minutes, hours, days, or continuously or intermittently, all subranges therebetween inclusive for all parameters.
The experimental protocol and animal use in this study were approved by the Animal Care and Use Committee at the University of Pittsburgh.
A total of 9 cats (4 females and 5 male, 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 (initial 65 mg/kg i.v. and supplemented as needed) during data collection. Left cephalic vein was catheterized for fluid administration. A tracheotomy was performed, and a tube was inserted to keep the airway patent. A catheter was inserted into right carotid artery to monitor systemic blood pressure. Heart rate and blood oxygen were monitored by a pulse oximeter (9847V; NONIN Medical, Plymouth, MN) attached to the tongue. Through an abdominal incision, one balloon catheter (G15766, Cook Urological, Spencer, IN) 1.4 cm in diameter and 5 cm in length was inserted into the proximal colon via a small incision at the proximal end of the colon (
The spinal cord was exposed from lumbar L7 to sacral S3 segments by a dorsal laminectomy. The dura mater was opened and each of the S1-S3 roots was identified. The dorsal and ventral roots were separated to either stimulate the ventral root individually or to stimulate both dorsal and ventral roots together. The animals were in a prone position during the experiment with a surgical retractor maintaining the spinal incision open to form a pool that was filled with warm (35-37° C.) mineral oil. A heating pad was used to maintain the animal body temperature between 35° C. and 37° C. Bipolar stainless steel hook electrodes (2-3 mm distance between the electrodes) were used to deliver the stimulation to each sacral spinal root by slightly lifting the root above the spinal cord.
In the first group of 7 cats, stimulation (7 Hz frequency, 0.2 ms pulse width, and 1 min duration) was delivered via the hook electrode to individual sacral ventral roots (S1, S2, or S3) at different intensity (1-16 V) to determine the intensity threshold (T) for inducing an observable pressure increase in the proximal colon. Then, an intensity (1.5-3T) that induced the maximal colon contraction was used to test colon responses to different stimulation frequencies (1-50 Hz). If no colon contraction was induced by stimulation of an individual ventral root, the maximal stimulation intensity that did not produce movement of the animal's lower body was used to test the frequency response. It was the study intention not to fix the hip and lower spine, so that sacral root stimulation by the hook electrode could produce local movement of the tail or hindlimb. However, the maximal stimulation intensity was limited by any movement of the lower spine, which would displace the hook electrode from the nerve. After stimulating each ventral root, the S2 ventral root which elicited the largest colon contraction was combined with the S2 dorsal root and the combination was stimulated with the most effective frequency (7 Hz.) The combined S2 root stimulation (1 minute duration) was applied 5 times at 1-minute intervals, and then followed by a continuous 5-minute stimulation to determine any fatigue in colon contraction.
In the second group of 2 cats, the combined S2 ventral and dorsal roots were stimulated (7 Hz) at an intensity that induced the largest colon contraction and for various durations (2.5-11 minutes) to determine if the stimulation could induce defecation, i.e., the evacuation of marbles that were inserted into the rectum. The defecation induced by S2 root stimulation was videotaped and the time of evacuation of the marbles was marked on the colon pressure recording.
To compare the colon contractions induced by stimulation of different ventral roots at different frequencies, the contraction amplitudes were always normalized to the maximal contraction amplitude induced by stimulation in the same animal. The colon contractions induced by the repeated 1-minute stimulations were normalized to the maximal contraction amplitude induced during the repeated simulations to determine repeatability. The maximal contraction amplitude induced during the 5-minute continuous stimulation and the contraction amplitude at the end of the 5-minute stimulation were compared to determine any fatigue during the continuous prolonged stimulation. The data from different animals are averaged and presented as means±SE. Statistical significance (p<0.05) was determined by paired t-test or repeated-measures ANOVA followed by Dunnett multiple comparison (one-way) or Bonferroni multiple comparison (two-way).
Stimulation of S2 ventral root induced larger colon contractions than stimulation of S1 or S3 ventral roots, and the most effective stimulation frequency was 7-10 Hz (
Stimulation (7 Hz) of the S2 ventral and dorsal roots together induced large amplitude (>20 cmH2O) contractions in both distal and proximal colon (
Stimulation of the S2 ventral and dorsal roots together induced a maximal amplitude colon contraction of 60 cmH2O in cat #1 (
This study in anesthetized cats shows that the colon response to sacral root stimulation is dependent on stimulation frequency and the spinal segment stimulated. S2 ventral root stimulation at 7 Hz is optimal to induce both proximal and distal colon contractions (
These results have significant implications for developing a new neuromodulation device to restore defecation function in humans after SCI. Since stimulation of the entire S2 spinal root (ventral and dorsal) is as effective as stimulation of the ventral root alone (
S2 ventral root stimulation eliminated all 4 marbles, but stimulation of S2 ventral and dorsal roots together only eliminated 1-2 marbles (
In this study the colon contraction and defection induced by S2 root stimulation always required a stimulation intensity higher than the intensity to induce hindlimb and/or tail movement. This result is expected because in cats the afferent and efferent nerve fibers in the S2 spinal root innervating the colon are small unmyelinated C-fibers that have higher excitation threshold than the large motor fibers. Since small C-fibers in the dorsal root are also involved in transmission of nociception, the stimulation intensity required for defection could also generate painful sensation at the same time. This should not be a critical issue for restoring defecation function in people with a complete SCI since they have no sensation below the level of the injury. However, it will be a problem to induce defecation for non-SCI people with chronic constipation if the extrinsic innervation of the human colon is similar to that in cats.
Recent application of sacral neuromodulation to treat non-SCI people with chronic constipation has generated inconclusive clinical outcome, which could be partially due to the use of a low stimulation intensity that only produces somatic sensations. This low stimulation intensity is probably not directly stimulating the nerve fibers in the sacral spinal root innervating the colon. However, it may modulate colon function indirectly by activating the large somatosensory fibers in the sacral root that can trigger central mechanisms to facilitate colon motility. This central modulation mechanism could be sensitive to stimulation frequency, but only a single stimulation frequency of 14 Hz was used in recent clinical trials to treat non-SCI people with chronic constipation. Our study shows that a lower frequency 7 Hz is optimal for sacral root stimulation to induce colon contractions, while other studies in rats and dogs found an effective frequency of 5 Hz or 10 Hz. Therefore, it seems that a frequency lower than 14 Hz should be tested in clinical studies to treat non-SCI people with chronic constipation.
Our study also shows that continuous stimulation can cause fatigue of colon contractions while intermittent stimulation is more fatigue resistant (
In summary, this study in cats optimized the stimulation parameters for sacral spinal root stimulation to induce colon contraction and defection. The results have significant implications for design of a novel neuromodulation device to restore defecation function after SCI, and for optimizing sacral neuromodulation parameters to treat non-SCI people with chronic constipation.
The experimental protocol and animal use in this study were approved by the Animal Care and Use Committee at the University of Pittsburgh.
A total of 8 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 (initial 65 mg/kg i.v. and supplemented as needed) during data collection. Left cephalic vein was catheterized for fluid administration. A tracheotomy was performed, and a tube was inserted to keep the airway patent. A catheter was inserted into right carotid artery to monitor systemic blood pressure via a pressure transducer (BLPR2 WPI, Sarasota, FL) connected to an amplifier (TBM4M, WPI, Sarasota, FL). Heart rate and blood oxygen were monitored by a pulse oximeter (9847V; NONIN Medical, Plymouth, MN) attached to the tongue. Through an abdominal incision, a catheter was inserted into the bladder via urethra to drain the bladder during the experiment and the urethra was tied with a suture. Then, the abdominal incision was closed with sutures.
The spinal cord was exposed from lumbar L7 to sacral S3 segments by a dorsal laminectomy. The dura mater was opened and each of the S1-S3 roots was identified. The dorsal and ventral roots were separated to either stimulate the ventral root individually or to stimulate both dorsal and ventral roots together (
At the beginning of the experiment, stimulation (30 Hz frequency, 0.2 ms pulse width, and 1-2 min duration) was delivered via the hook electrode to sacral S1 ventral root at a minimal intensity (0.5 V). If no erection was observed, the stimulation intensity was increased and then tested again until a penile erection was observed. If S1 ventral root stimulation was not effective, then the stimulation electrode was moved to the S2 ventral root, and the test was repeated. A penile erection, which was evident as a full protrusion of the penis with rigidity resistant to bending, was always observed by stimulation of the individual S1 and S2 ventral roots. After the 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 the erection (
After placement of the penile catheter (N=8 cats), stimulation (30 or 40 Hz frequency, 0.2 ms pulse width, and 1 min duration) was delivered via the hook electrode to individual left or right sacral ventral roots (S1, S2, or S3) at a range of intensities (0.5-15 V) to determine the intensity threshold (T) for inducing an observable increase in penile pressure. Then, an intensity (1.5-3T) that induced the maximal penile pressure (>100 cmH2O) was used to test penile responses to different stimulation frequencies (5-80 Hz). If no penile pressure >100 cmH2O was induced by stimulation of an individual ventral root, the maximal stimulation intensity that did not produce movement of the animal's lower body was used to test the frequency response. It was intended not to fix the hip and lower spine, so that sacral root stimulation by the hook electrode could produce local movement of the tail or hindlimb. However, the maximal stimulation intensity was limited by any movement of the lower spine, which would displace the hook electrode from the nerve. After testing each ventral root, the ventral root (S1 or S2) that elicited the largest penile pressure was combined with the dorsal root and the combination was stimulated continuously for 10 mins with the most effective frequency (30 Hz) and intensity to determine if the induced penile erection was sustainable during the entire stimulation period. Finally, the spinal cord was completely transected at the T9-T10 level (N=6 cats). About 10 minutes after the spinal cord transection, the continuous 10-minute stimulation of the same spinal root (ventral and dorsal roots together) was tested again to induce penile erection. No drug was used to treat the blood pressure change caused by the spinal transection.
To compare the penile erection responses induced by stimulation of different ventral roots at different frequencies, the maximal amplitudes of the penile pressure induced by stimulation were measured and averaged across different animals for the same stimulation conditions. To determine the sustainability of the induced penile election, the maximal penile pressure induced by the continuous 10-minute stimulations was compared to the pressure at the end of the 10-minute stimulation. To determine the effect of the spinal cord transection, the maximal penile pressures induced by the continuous 10-minute stimulation were compared before and after the spinal cord transection. The data from different animals are averaged and presented as means±SE. Paired t-test or repeated-measures Friedman test followed by Dunnett's multiple comparison were performed for statistical analysis using a software package (Prism 9.3.1, GraphPad Software, San Diego, CA). The statistical significance was defined as p<0.05.Results
Penile erection was observed as a full protrusion of the penis with rigidity in 6 cats by stimulation of S1 ventral root (S2 and S3 ineffective) and in 2 cats by stimulation of S2 ventral root (S1 and S3 ineffective). The stimulation parameters were 30 Hz frequency, 0.2 ms pulse width, and intensity 4.3±1.0 V (0.5-8 V). These responses which were quantified by penile pressure recordings showed that S1 or S2 ventral root stimulation in 6 cats and 2 cats, respectively, induced a large increase in penile pressure from the baseline pressure of 25±1 cmH2O to 177±14 cmH2O (S1) or 147±2 cmH2O (S2) (
Continuous 10-minute stimulation (30 Hz) of the S1 or S2 spinal root (i.e., ventral and dorsal roots together) induced a large increase in penile pressure (190±8 cmH2O) (
After a complete spinal cord transection at the T9-T10 level, continuous 10-minute stimulation (30 Hz) of the S1 or S2 spinal root (ventral and dorsal roots together) also induced a large increase (186±9 cmH2O) in penile pressure (
This study in anesthetized cats shows that the penile erection induced by sacral root stimulation is dependent on stimulation frequency and the spinal segment stimulated. In each animal one spinal root, most often S1, which contains a minor component of the parasympathetic efferent outflow to the pelvic viscera in the cat, elicited the most prominent response. The largest increases in penile pressure occurred at 30-40 Hz stimulation (
Previous studies have shown that penile erection can be induced by electrical stimulation of pelvic nerve, cavernous nerve, or dorsal penile nerve in mice, rats, cats, dogs, monkeys, or humans. However, the pelvic and cavernous nerves require invasive surgery for implantation of stimulation electrodes while the dorsal penile nerve is not a convenient location to attach a stimulation electrode during sexual intercourse. Therefore, these stimulation methods are not broadly adopted for clinical application 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 using cats and dogs. In addition, sacral anterior root stimulation was used to restore bladder function and erectile function for some SCI people. However, invasive spinal surgery is required to implant the stimulation electrodes on the sacral anterior roots, preventing this effective treatment to be used in SCI or non-SCI people for the sole purpose of treating erectile dysfunction. This study in cats indicates that penile erection can be induced by stimulation of the sacral spinal roots. A previous study in dogs also showed a similar effect. The significance of stimulating the sacral spinal root instead of the ventral root lies in the potential to employ a minimally invasive surgical approach for stimulation. Sacral spinal roots in humans are accessible by inserting a foramen needle percutaneously to deploy a stimulating lead electrode. This surgical approach has been routinely used in sacral neuromodulation therapy for overactive bladder. Therefore, the present study has significant implications for developing a new sacral neuromodulation therapy using a minimally invasive surgical approach to restore erectile function for both SCI and non-SCI people.
Previous studies using sacral neuromodulation to treat overactive bladder also evaluated the effects on penile erection in both SCI and non-SCI people. Questionnaires indicate that subjects with moderate-mild erectile dysfunction significantly improved their quality of sexual life by sacral neuromodulation therapy. However, these studies used stimulation parameters optimized to treat overactive bladder, i.e., stimulation frequency 20 Hz at the sensory threshold intensity. These stimulation parameters may not be optimal for the treatment of erectile dysfunction because the study indicates that a higher stimulation frequency (30-40 Hz) at intensities above sensory and motor thresholds can induce penile erection quickly once the stimulation is turned on and the erection can be sustained during the entire 10-minute stimulation. This type of on-demand erection should be much more satisfactory for the patient than the quality-of-life improvement produced by continuous (24 hours×7 days) sacral neuromodulation at a lower frequency and weaker stimulation intensity. Therefore, it seems that a higher frequency (30-40 Hz) and a stronger stimulation intensity (above sensory and motor thresholds) should be tested in clinical studies to treat erectile dysfunction. Although leg movement will be induced by a stronger stimulation, the leg muscle contraction will be tonic and the movement will only occur at the beginning of the stimulation, which should not be a problem for successful sexual intercourse. When anterior root stimulation was used to induce penile erection in SCI people, it also induced leg movement but did not prevent successful sexual intercourse.
Stimulation of the sacral spinal root (ventral and dorsal roots together) induced a large increase in penile pressure similar to that produced by stimulation of the ventral root alone (
This study shows that the penile erection induced by sacral root stimulation is sustainable or gradually develops during the 10-minute stimulation (
While the present invention has been described in terms of the above detailed description, those of ordinary skill in the art will understand that alterations may be made within the spirit of the invention. Accordingly, the above should not be considered limiting, and the scope of the invention is defined by the appended claims.
This application claims the benefit of U.S. Provisional Patent Application No. 63/255,606, filed Oct. 14, 2021, which is incorporated herein by reference in its entirety.
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.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/040037 | 8/11/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63255606 | Oct 2021 | US |
