CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Application No. 63/252,528 filed October 5, 2021, the disclosure of which is hereby incorporated in its entirety by reference herein.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with Government support under W81XWH-15-C-0066, awarded by U.S. Department of Defense, U.S. Army Medical Research Acquisition Activity. The Government has certain rights in the invention.

TECHNICAL FIELD

[0003] The present inventions relate to systems and methods for the treatment of physiological disorders and the restoration and enhancement of bodily functions through the concurrent electrical modulation of nerves or muscle using multiple independent channels.

BACKGROUND

[0004] Electrical neuromodulation is used to deliver long-term electrical therapy to alleviate a wide range of chronic diseases and symptoms, such as persistent pain, spasticity, movement disorders, epilepsy, ischemia, cardiac dysfunction, bowel dysfunction, bladder dysfunction, spinal injury, and visual, auditory, and specific psychiatric disorders. Traditionally, only one channel of an electrical neuromodulation system has been used to either block a perceived signal, such as pain, or to stimulate a muscle or set of muscles to promote a desired condition or modulate autonomic activity, such as relaxing the bladder to increase capacity for an over-active bladder. Multiple independent channels have also been used for sequential excitation of targeted nerves, in which only one independent channel is active at a given time to either stimulate, block, or do both in time-sequence, but not concurrently.

[0005] However, to achieve a desired physiological response with an electrical neuromodulation system, sometimes multiple independent channels need to be concurrently energized. With such a system, it is important that any undesirable physiological response that could be caused by the stimulation itself, including unwanted stimulation and nerve damage, is minimized or eliminated. These undesirable effects are caused by undesirable action potential generation and propagation from concurrently activated independent channels, and their electrical interactions and effects. These undesirable action potentials could also interfere with, and sometimes even prevent, the desired physiological response.

[0006] Thus, there remains a need to enable a concurrent, yet independent, multi-channel neuromodulation system that minimizes undesirable action potential generation and propagation.

SUMMARY

[0007] In accordance with a first aspect of the present inventions, an electrical neuromodulation system comprises signal output circuitry comprising an N number of channels. In one embodiment, the signal output circuitry comprises another channel that is dependent on at least one of the N number of channels. The electrical neuromodulation system further comprises at least an N-l number of electrical isolators (e.g., transformers) configured for respectively isolating an N-l number of the independent channels (e.g., using electrical means, mechanical means, chemical means, thermal means, magnetic means, or a combination thereof), such that the N number of channels have different grounds.

[0008] The electrical neuromodulation system further comprises processing circuitry configured for independently controlling the signal output circuitry to concurrently deliver neuromodulation energy in accordance with at least two different sets of neuromodulation parameters through the N number of channels to at least one anatomical site inside of a patient. For example, one of the at least two different sets of neuromodulation parameters may comprise a frequency in the range of 1 Hz to 100 Hz, and another one of the two different sets of neuromodulation parameters may comprise a frequency in the range of 2 kHz to 20 kHz.

[0009] In one embodiment, the N-l number of electrical isolators are located at an output of the signal output circuitry. In one specific example of this embodiment, each of the N-l number of electrical isolators is a ferrite-core transformer with an operating frequency in the kHz range. In another embodiment, the N-l number of electrical isolators are located between an input of the signal output circuitry and the processing circuitry. In one specific example of this other embodiment, each of the N-l number of electrical isolators is configured for transferring power to the signal output circuitry, and the electrical neuromodulation system further comprises an N-l number of optical signal isolators respectively configured for relaying control signals from the processing circuitry to the signal output circuitry. Each of the N-l number of electrical isolators may be, e.g., one of a piezo-electrical transformer and a DC-to-DC converter with an operating frequency in the MHz range.

[0010] In another embodiment, the electrical neuromodulation system further comprises an N number of electrode assemblies respectively electrically coupled to the N number of channels of the signal output circuitry. In one embodiment, each of the N number of electrode assemblies is a cuff electrode assembly. The cuff electrode assembly may, e.g., be sized to be circumferentially disposed around at least 75% of a peripheral nerve. Each cuff electrode assembly of at least one of the N number of electrode assemblies may be a bipolar cuff electrode assembly, and the cuff electrode assembly of at least another one of the N number of electrode assemblies may be a tripolar cuff electrode assembly. In this case, the bipolar cuff electrode assembly may comprise two electrical electrodes having a spacing, such that the two electrical electrodes overlap at least one Node of Ranvier of a peripheral nerve, and the tripolar cuff electrode assembly may comprise three electrical electrodes having spacings, such that the three electrical electrodes span at least one Node of Ranvier of the peripheral nerve. In one example, a first one of the at least two different sets of neuromodulation parameters may comprise a first frequency in the range of 1 Hz to 100 Hz, such that the neuromodulation energy is delivered through at least a first one of the N number of channels to the at least one bipolar cuff electrode assembly at the first frequency, and a second one of the at least two different sets of neuromodulation parameters may comprise a second frequency in the range of 2 kHz to 20 kHz, such that the neuromodulation energy is delivered through at least a second one of the N number of channels to the at least one bipolar cuff electrode assembly at the second frequency.

[0011] The electrical neuromodulation system further comprises a biocompatible casing containing the signal output circuitry, and the N-l number of electrical isolators. In one embodiment, the electrical neuromodulation system further comprises a battery configured for supplying power to the signal output circuitry and the processing circuitry, in which case, the biocompatible casing further may contain at least a portion of the processing circuitry and the battery.

[0012] In one optional embodiment, the electrical neuromodulation system further comprises monitoring circuitry configured for sensing an electrical parameter at a non-isolated side of each of the N-l electrical isolators. In this case, the processing circuitry may be configured for estimating an intensity level of the delivered neuromodulation energy at the isolated side of each of the N-l electrical isolators based on the sensed electrical parameter at the non-isolated side of each of the N-l electrical isolators. In this embodiment, each of the N number of channels may have an adjustable power supply, in which case, the processing circuitry may be configured for varying the adjustable power supply of each of the N-l number of channels based on the estimated intensity level of the neuromodulation energy at the isolated side of each of the N-l electrical isolators, such that an intensity level of the delivered neuromodulation energy for each of the N-l channels is within a set intensity level range for each of the N-l channels. In one example of this embodiment, the adjustable power supply may be an adjustable voltage supply, and the sensed electrical parameter may be a sensed electrical current. In this example, the processing circuitry may be configured for estimating an impedance load at the isolated side of each of the N-l electrical isolators based on the sensed electrical current at the non-isolated side of each of the N-l electrical isolators (e.g., by inputting a frequency and voltage into a model characterizing each of the N-l channels and the N-l electrical isolators), and estimating the intensity level of the delivered neuromodulation energy at the isolated side of each of the N-l electrical isolators based on the estimated impedance load at the isolated side of each of the N-l electrical isolators and an output voltage of the adjustable voltage supply of each of the N-l channels. [0013] In accordance with a second aspect of the present inventions, a method of neuromodulating at least one anatomical site inside a patient using an implantable pulse generator (IPG) implanted within the patient is provided. The method comprises concurrently delivering neuromodulation energy from the IPG through an N number of channels to the at least one anatomical site in accordance with at least two different sets of neuromodulation parameters, and electrically isolating an N-l number of the independent channels, such that the N number of independent channels have different grounds.

[0014] In one method, the patient suffers from urinary dysfunction, and the concurrent delivery of the neuromodulation energy to the anatomical site(s) may treat the urinary dysfunction. In this method, the anatomical site(s) may be located on at least one nerve arising out of the sacral system of the patient (e.g., at least one pudendal nerve or at least one of the major branches of the at least one pudendal nerve), such that the concurrent delivery of the neuromodulation energy to the nerve(s) promotes efficient voiding of a bladder of the patient. In one specific implementation, the urinary dysfunction is Detrusor Sphincter Dyssynergia. In this case, the concurrent delivery of neuromodulation energy from the IPG through the N number of channels to the pudendal nerve(s) may comprise concurrently delivering the neuromodulation energy through a first one of the N number of channels in accordance with a first of the at least two different sets of neuromodulation parameters (e.g., a pulse amplitude in the range of 0.05 mA to 10 mA, a frequency in the range of 1 Hz to 100 Hz, and a pulse width in the range of 120 ps to 1980 ps) to promote bladder contraction and through at least a second one of the N number of channels in accordance with at least a second of the at least two different sets of neuromodulation parameters (e.g., a frequency in the range of 2 kHz to 20 kHz and an amplitude in the range of 0.2 mA to 14 mA) to block an external urinary sphincter (EUS) from contracting, thereby allowing efficient voiding of the bladder. The second one(s) of the N number of channels may comprise second and third ones of the N number of channels, the pudendal nerve(s) may comprise a left pudendal nerve and a right pudendal nerve, and the neuromodulation energy may be bilaterally delivered through the second and third ones of the N number of channels to the left pudendal nerve and the right pudendal nerve proximal to the EUS. An optional method further comprises delivering neuromodulation energy from the IPG through the first one of the N number of channels to one of the pudendal nerve(s) in accordance with a set of neuromodulation parameters different from the at least two different sets of neuromodulation parameters, thereby promoting filling of the bladder.

[0015] Other and further aspects and features of the invention will be evident from reading the following detailed description of the preferred embodiments, which are intended to illustrate, not limit, the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The drawings illustrate the design and utility of embodiments of the present invention, in which similar elements are referred to by common reference numerals. In order to better appreciate how the above-recited and other advantages and objects of the present inventions are obtained, a more particular description of the present inventions briefly described above will be rendered by reference to specific embodiments thereof, which are illustrated in the accompanying drawings. Understanding that these drawings depict only typical embodiments of the invention and are not therefore to be considered limiting of its scope, the invention will be described and explained with additional specificity and detail through the use of the accompanying drawings in which:

[0017] Fig. 1 is a block diagram of an exemplary micturition management system constructed in accordance with one embodiment of the present inventions;

[0018] Fig. 2A is a profile view of one embodiment of an implantable pulse generator (IPG) used in the micturition management system of Fig. 1;

[0019] Fig. 2B is a perspective view of the IPG of Fig. 2A, particularly showing leads being inserted into the IPG;

[0020] Fig. 3 is a block diagram of the internal electronic componentry of the IPG of Figs. 2A and 2B; [0021] Fig. 4 is an anatomical diagram of sacral nerves, and its branches, in a patient on which the electrode assemblies of the micturition management system of Fig. 1 are to be attached;

[0022] Fig. 5 is a diagram illustrating the location of lead electrode assemblies of the micturition management system of Fig. 1 on the left and right sides of the pudendal nerve of a patient;

[0023] Fig. 6 is a diagram illustrating the neuromodulation pathways in the patient that may be activated when concurrently activating the lead electrodes illustrated in Fig. 5 during a Void Mode of the micturition management system of Fig. 1;

[0024] Fig. 7 is a timing diagram illustrating an exemplary neuromodulation sequence of the micturition management system of Fig. 1 during operation of one cycle of a Fill Mode and a Void Mode;

[0025] Fig. 8 is a diagram illustrating potential cross-talk pathways in the patient if the micturition management system of Fig. 1 is operated during a Void Mode without channel isolation;

[0026] Fig. 9 is an electrical schematic diagram illustrating a conventional single-channel neuromodulation system in use with a patient;

[0027] Fig. 10 is an electrical schematic diagram illustrating a conventional transcutaneous multi-channel neuromodulation system in use with a patient, particularly showing a potential cross-talk pathway between non-isolated channels;

[0028] Fig. 11 is an electrical schematic illustrating another conventional transcutaneous multi-channel neuromodulation system in use with a patient, particularly showing a potential cross-talk pathway between non-isolated channels;

[0029] Fig. 12 is an electrical schematic diagram illustrating a conventional fully implantable multi-channel neuromodulation system in use with a patient, particularly showing a potential cross-talk pathway between non-isolated channels; [0030] Fig. 13 is an electrical schematic diagram illustrating the conventional fully implantable multi-channel neuromodulation system of Fig. 12, particularly showing no cross-talk between the non-isolated channels when sequentially activated;

[0031] Fig. 14 is an electrical schematic diagram illustrating the conventional fully implantable multi-channel neuromodulation system of Fig. 12, particularly showing minimal cross-talk between the non-isolated channels when concurrently activated with the same neuromodulation parameters;

[0032] Fig. 15 is an electrical schematic diagram illustrating the conventional fully implantable multi-channel neuromodulation system of Fig. 12, particularly showing significant cross-talk between the non-isolated channels when concurrently activated with different neuromodulation parameters;

[0033] Fig. 16A is a cross-sectional view of one embodiment of a cuff electrode of the micturition management system of Fig. 1, circumferentially disposed around a target peripheral myelinated nerve;

[0034] Fig. 16B is a cross-sectional view of an alternative embodiment of a side electrode of the micturition management system of Fig. 1, disposed on a target peripheral myelinated nerve;

[0035] Fig. 17 is a longitudinal- sectional view of a peripheral myelinated nerve, particularly showing Nodes of Ranvier that accelerate conduction velocity of action potential propagation;

[0036] Fig. 18 is a view of a myelinated nerve with key dimensions of inter-nodal distance (Y) and nerve diameter (X);

[0037] Fig. 19A is a plan view of one embodiment of an unfurled bipolar nerve cuff electrode of the micturition management system of Fig. 1;

[0038] Fig. 19B is a plan view of one embodiment of an unfurled tripolar nerve cuff electrode of the micturition management system of Fig. 1; [0039] Fig. 20 is a view illustrating bidirectional stimulation of a pudendal nerve with the bipolar nerve cuff electrode of Fig. 19A;

[0040] Fig. 21 A is a cross-sectional view of a nerve showing an electrical field generated inside a target peripheral myelinated nerve by the activation of the bipolar nerve cuff electrode of Fig. 19A;

[0041] Fig. 2 IB is a longitudinal- sectional view of a nerve showing an electrical field generated, both inside and outside a target peripheral myelinated nerve, by the activation of the bipolar nerve cuff electrode of Fig. 19A;

[0042] Fig. 22 is a view illustrating bidirectional blocking of a nerve via the activation of the tripolar nerve cuff electrode of Fig. 19B;

[0043] Fig. 23A is a cross-sectional view of a nerve showing an electrical field generated by the activation of the tripolar nerve cuff electrode of Fig. 19B;

[0044] Fig. 23B is a longitudinal- sectional view of a nerve showing an electrical field generated in the nerve by the activation of the tripolar nerve cuff electrode of Fig. 19B;

[0045] Fig. 24 is an electrical schematic diagram illustrating one approach for electrically isolating channels in a transcutaneous multi-channel neuromodulation system;

[0046] Fig. 25 is an electrical schematic diagram illustrating another approach for electrically isolating channels in a transcutaneous multi-channel neuromodulation system;

[0047] Fig. 26 is an electrical schematic diagram illustrating still another approach for electrically isolating channels in a transcutaneous multi-channel neuromodulation system;

[0048] Fig. 27 is an electrical schematic diagram illustrating one approach for electrically isolating channels in a fully implantable multi-channel neuromodulation system;

[0049] Fig. 28 is a block diagram illustrating one channel isolation technique that can be implemented in the micturition management system of Fig. 1; [0050] Fig. 29 is a diagram illustrating one example of the channel isolation technique of

Fig. 28;

[0051] Fig. 30 is a schematic diagram illustrating the location of the lead electrode assemblies of Bipolar Channel CHI and Tripolar Channels CH2-CH3 of the micturition management system of Fig. 1 on a pudendal nerve;

[0052] Fig. 31 is a circuit diagram of Bipolar Channel CHI and Tripolar Channels CH2- CH3 of Fig. 30 when there is no electrical channel isolation;

[0053] Fig. 32 is a circuit diagram of a transformer used for each isolated channel in the channel isolation technique of Fig. 29;

[0054] Fig. 33 is a circuit diagram of Bipolar Channel CHI and Tripolar Channels CH2- CH3 of Fig. 30 when there is electrical channel isolation using the transformer of the channel isolation technique of Fig. 29;

[0055] Fig. 34 is a block diagram illustrating another method to implement the channel isolation technique of Fig. 28;

[0056] Fig. 35 is a diagram illustrating one example of the channel isolation technique of Fig. 34 using a DC/DC converter for power isolation and opto-electronics for signal isolation;

[0057] Fig. 36 is a diagram illustrating another example of the channel isolation technique of Fig. 34 using a piezo-electric converter for power isolation and opto-electronics for signal isolation;

[0058] Fig. 37 is a diagram illustrating still another example of the channel isolation technique of Fig. 34;

[0059] Fig. 38 is a diagram illustrating the modeled internal components of Tripolar Channel CH2 or Tripolar Channel CH3 of the IPG of Figs. 2A and 2B;

[0060] Fig. 39 is a circuit diagram of an equivalent circuit of a transformer used to isolate Tripolar Channels CH2-CH3 in the IPG of Figs. 2A and 2B; [0061] Fig. 40 is a diagram of observed measurements of the primary leakage inductance per the equivalent circuit of Fig. 39 of the transformer used to isolate Tripolar Channels CH2- CH3 in the IPG of Figs. 2A and 2B, plotted over a frequency range;

[0062] Fig. 41 is a diagram of observed measurements of the parallel resistance per the equivalent circuit of Fig. 39 of a component of the transformer used to isolate Tripolar Channels CH2-CH3 in the IPG of Figs. 2A and 2B, plotted over a frequency range;

[0063] Fig. 42 is a diagram of observed measurements of the primary capacitance per the equivalent circuit of Fig. 39 of a component of the transformer used to isolate Tripolar Channels CH2-CH3 in the IPG of Figs. 2A and 2B, plotted over a frequency range;

[0064] Fig. 43 is a diagram of observed measurements of the resistance of a switch used in Tripolar Channel CH2 or Tripolar Channel CH3 plotted over a voltage range;

[0065] Fig. 44 is a manufacturer’s I-V graph of diodes used in the Tripolar Channel CH2 or Tripolar Channel CH3 ;

[0066] Fig. 45 is a flow diagram illustrating one exemplary method of operating the micturition management system of Fig. 1; and

[0067] Fig. 46 is a flow diagram illustrating one method of adaptively adjusting an amperage level of neuromodulation energy delivered by the micturition management system of Fig. 1.

DETAILED DESCRIPTION

[0068] Normal functions of the lower urinary tract are storage and periodic elimination of urine. During storage, the detrusor is relaxed while the urethral sphincter maintains its normal contracted state. During voiding the detrusor contracts and the urethral sphincter is relaxed. However, after spinal cord injury (SCI), there is a paralysis of muscles below the level of injury primarily caused by destruction or damage to neural pathways. When neural pathways that govern the urinary tract are damaged, the bladder will be impaired in its function resulting in neurogenic bladder, a condition that may include symptoms, such as frequent urination, urinary incontinence, and retention.

[0069] Most patients with SCI have bladder dysfunction, with detrusor over-activity (DO) and detrusor sphincter dyssynergia (DSD) being the common abnormalities (see Game, Xavier, et al., “Neuropathic Bladder Dysfunction,” Trends in Urology Gynecology & Sexual Health, pp. 23-28 (2010)). DO is defined as involuntary detrusor contraction during bladder filling resulting in a sudden urge to urinate (see Henderson, Emily, et al., “Overactive Bladder,” Maturitas, pp. 257-262 (2010)). DSD is defined as the impaired coordination between detrusor and sphincter during voiding due to a neurologic abnormality and is commonly characterized by involuntary contractions of the external urethral sphincter during an involuntary detrusor contraction (see Bascu, CD, et al., “Diagnosing Detrusor Sphincter Dysynergia in the Neurological Patient,” British Journal of Urology International, pp. 31-34 (2012)). DSD generates high bladder pressures, prevents complete elimination of urine and requires daily urethral catheterization (see Bums, A.S., et al., “The Management of Neurogenic Bladder and Sexual Dysfunction After Spinal Cord Injury,” Spine, 26: sl29 (2001)). Other causes of DSD besides SCI include Multiple Sclerosis, Spina Bifida, Transverse Myelitis, Cerebral Palsy, Stroke and other central nervous system pathologies.

[0070] Prior to World War II, SCI was almost universally fatal, with urosepsis or urinary tract infection (UTI) being the predominant cause of death. UTI results from inadequate bladder emptying, which leaves large residual volumes of urine in the bladder. The high bladder pressures that build up from the inability to void voluntarily lead to autonomic dysreflexia, vesicoureteral reflux, upper urinary tract dilatation, renal stone formation and hydronephrosis, eventually resulting in renal failure. From autopsies on 122 paraplegic patients, it was found that 52% of the deaths were secondary to renal failure (see Tribe, C.R., “Cause of Death in Early and Late Stages of Paraplegia,” Spinal Cord, pp. 19-47 (1963)).

[0071] After SCI, the bladder’s storage function is generally preserved via the spinal reflexes, but excitatory input to the bladder and inhibitory input to the external urethral sphincter from the brain during voiding are commonly lost. Abnormalities observed after SCI also include afferent pelvic and pudendal nerve signals now capable of initiating detrusor contraction and a loss of pudendal efferent inhibition (see Tai, C., et al., “Spinal Reflex Control of Micturition After Spinal Cord Injury,” Resto Neurol Neurosci, pp. 69-78 (2006)). In short, after SCI, pelvic and pudendal afferents are capable of driving competing systems (voiding/storage) in the bladder producing symptoms of DO and DSD.

[0072] In addition to the physiological health sequelae, psychological health after SCI is equally as important to consider with psychological diagnosis warranting intervention from a clinical psychologist and/or psychiatrist occurring in up to 40% of the SCI population. Changes that are reported after SCI include: lack of privacy, loss of independence, changes to role / lifestyle, uncertainty regarding the future, sense of helplessness, and separation from family and friends (see Agency for Clinical Innovation, “Psychological Adjustment after Spinal Cord Injury,” ACI (2014)). Bladder management after SCI is a major contributor to these psychological sequelae and according to a 2012 study, the desire to regain bladder control outranks even the desire to walk again for SCI persons (see Simpson, LA, “The Health and Life Priorities of Individuals with Spinal Cord Injury: A Systematic Review,” J Neurotrauma, pp. 1548-55 (2012).

[0073] Pharmacological therapy is the first step in treating DO associated with SCI with antimuscarinic drugs, such as oxybutynin and tolterodine, among the first line therapies. However, these pharmacotherapies are often unsuccessful and are limited by side effects, such as dry mouth, blurred vision, and constipation (see Chapple, C.R., “Muscarinic Receptor Antagonist in the Treatment of Overactive Bladder,” Urology, pp. 33-46 (2000)).

[0074] No currently marketed medication or device is capable of treating DSD, and the mainstay of treatment for DSD is clean intermittent catheterization. Although catheterization has been found to be effective in managing DSD, indwelling urethral or suprapubic catheters have been associated with urinary tract infections (UTIs), upper tract deterioration and renal failure. Studies have shown a 10% prevalence of asymptomatic urinary tract infection and a more than 50% prevalence of symptomatic urinary tract infection with catheterization (see Wyndaele, J. J., “Complications of Intermittent Catheterization: Their Prevention and Treatment,” pp. 536-541 (2002)). The reported rate of UTI is approximately 5% to 7% for each day of catheterization and there is up to 100% incidence of significant bacteriuria associated with long-term indwelling catheters (see Scheffer, A. J., “Catheter Associated Bacteruria,” Urologic Clinics of North America, p. 735 (1986)). Although a preferred method of bladder management in patients who have good hand coordination, intermittent catheterization is also not without complications. With every catheter insertion, there is a risk of bacteriuria and UTI. The risk of infection is lower with intermittent catheterization than with an indwelling catheter; however, 70% of patients maintained on long-term self-intermittent catheterization suffer from UTIs (see Maynard, et al., “The Prevention and Management of Urinary Tract Infections Among People with Spinal Cord Injuries,” Journal of American Paraplegia Society, p. 194 (1992); McGuire, E.J., et al. (“Long-Term Follow-Up of Spinal Cord Injured Patients Managed by Intermittent Catheterization,” Journal of Urology, p. 775 (1983)); Stover, S.L., et al., “Neurogenic Urinary Tract Infection,” Neurologic Clinics, p. 741 (1991)).

[0075] In addition to catheterization, pharmacological therapies are often prescribed for DSD, most commonly in the form of alpha-adrenergic blockers and antispasmodics; however, there is limited data to support their efficacy (see Stoffel, J.T., “Detrusor Sphincter Dyssynergia: A Review of Physiology, Diagnosis, and Treatment Strategies,” Translational Andrology and Urology, pp. 127-135 (2016)).

[0076] Other current treatments of DSD include transurethral sphincterotomy (see Catz, A., Luttwak, et al, “The Role of External Sphincterotomy for Patients with Spinal Cord Lesion,” Spinal Cord, 35: 48 (1997)), and injection of the urethral sphincter with botulinum A toxin (BOTOX®) (see Yoshimura, N., Smith, “Pharmacologic and Potential Biologic Interventions to Restore Bladder Function After Spinal Cord Injury,” Curr Opin Neurol, 13: 677 (2000)).

[0077] Sphincterotomy is effective, but it may induce permanent incontinence and longterm failure has been reported (see Vapnek, J. M., Couillard, et al., “Is sphincterotomy the Best Management of the Spinal Cord Injured Bladder?,” J Urol, 151: 961 (1994)). Though effective at reducing urethral pressure and decreasing post-void residual volume, the therapeutic effect of botulinum A toxin injected into the external urethral sphincter is limited and treatment must be repeated frequently (see Stoffel, J.T., “Detrusor Sphincter Dyssynergia: A Review of Physiology, Diagnosis, and Treatment Strategies,” Translational Andrology and Urology, pp. 127-135 (2016)). In addition, little is known about the effects of repeated injections, and with repeated use of botulinum A toxin there might be a risk of inducing the immunization against the toxin (see Schmid, D.M., et al., “Prospects and Limitations of Treatment with Botulinum Neurotoxin A for Patients with Refractory Idiopathic Detrusor Overactivity,” BJU Int, pp. 7-10 (2008).

[0078] Other procedures, such as balloon dilation of the external urethral sphincter (see Chancellor, M.B., et al., “Prospective Comparison of External Sphincter Balloon Dilatation and Prosthesis Placement with External Sphincterotomy in Spinal Cord Injured Men,” Arch Phys Med Rehab, 75: 297 (1994), intraurethral stent placement (see Chancellor, M.B., et al., “Longterm Followup of the North American Multicenter UroLume Trial for the Treatment of External Detrusor-Sphincter Dyssynergia,” J Urol, 161: 1545, (1999)), and local application of 5% to 7% phenol solution to block the pudendal nerve (see Tsai, S. J., et al., “Treatment of Detrusor- Sphincter Dyssynergia by Pudendal Nerve Block in Patient with Spinal Cord Injury,” Arch Phys Med Rehabil, 83: 714 (2002)) have been tested for the treatment of DSD.

[0079] However, a stent in the urethra causes frequent infection (see Bums, A.S., et al., “The Management of Neurogenic Bladder and Sexual Dysfunction After Spinal Cord Injury,” Spine, 26: sl29 (2001)). Calculus formation in the stent and its migration also cause problems (see Chancellor, M.B., et al., “Long-term Followup of the North American Multicenter UroLume Trial for the Treatment of External Detrusor-Sphincter Dyssynergia,” J Urol, 161: 1545 (1999)). Although the treatment of locally applying phenol solution to block the pudendal nerve is effective for decreasing sphincter hypertonicity, it never completely relaxed the sphincter during voiding, because the nerves were only partially blocked to maintain continence during urine storage.

[0080] One promising treatment for bladder dysfunction, such as DO and DSD, is electrical neuromodulation. Neuromodulation can be defined as a field of science, medicine, and bioengineering that encompasses implantable and non-implantable technologies that impact upon neural interfaces towards a desired physiological or psychological effect. As a result of an increasing number of applications, the field of neuromodulation is constantly growing and evolving. It not only comprises the use of electrical and magnetic stimulation, but also chemical and genetic manipulations. As such, techniques capable of modulating the activity of neural elements without ablating or injuring the nervous system are now included under the umbrella of neuromodulation (see Krames, Elliot S., et. al., “What is Neuromodulation?”, Neuromodulation, pp. 3-8 (2009); Hamani, Clement, et al., “Neuromodulation: A More Complete Concept Beyond Deep Brain Stimulation,” pp. 1-3 (2012)).

[0081] Chemical neuromodulation uses direct placement of chemical agents, such as an antispastic or pain relief agent to neural tissues through utilization of technology of implantation, such as epidural or intrathecal delivery systems. Neuromodulation using medication works by delivering directly to a target site through a catheter and pump, minimizing the dose needed and potential side effects. In the case for treating DSD, delivering botulinum A toxin to the external urinary sphincter or phenol solution to the pudendal nerve may be considered chemical neuromodulation .

[0082] Electrical neuromodulation is electrical modulation of the brain, spinal cord, peripheral nerves, plexuses of nerves, the autonomic system, and functional electrical modulation of the muscles.

[0083] Many electrical neuromodulation therapies target the brain and spinal cord — the root of the nervous system — to deliver pain relief or restore function. Peripheral nerve modulation, meanwhile, targets electrical impulses elsewhere in the body, such as the limbs. As a therapy, electrical neuromodulation is inherently reversible and adjustable.

[0084] The modem era of neuromodulation began in the early 1960s, first with deep brain stimulation which was soon followed (in 1967) by spinal cord stimulation, both for otherwise intractable pain. The gradual realization that pain was the result of complex dynamic processes in the nervous system and not simply the result of activity in a hard-wired system was greatly enhanced by the publication of the Gate Theory in 1965. As damage to the nervous system can itself cause chronic pain, there began a gradual move away from destructive surgical treatments such as cutting nerves and towards reversible, modulatory treatments: neuromodulation .

[0085] Attempts to electrically control the bladder via electrical neuromodulation originated as early as the 1960s. These efforts have targeted the spinal center for micturition control as well as the bladder itself. [0086] For example, with respect to the treatment of DO, one neuromodulation technique, and in particular sacral nerve stimulation, has been approved for management of overactive bladder (OAB) symptoms, and has gained popularity in recent years. For example, marketed devices, such as Medtronic’s Interstim® target the S3 nerve root. Although sacral nerve stimulation can provide long lasting bladder inhibition in incontinent patients with an intact spinal cord, only short lasting inhibitory effects have been reported in DO caused by SCI (see Previnaire, J.R., et al., “Is There a Place for Pudendal Nerve Maximal Electrical Stimulation for the Treatment of Detrusor Hyperreflexia in Spinal Cord Injury Patients,” Spinal Cord, pp. 100-103 (1998); Chartier-Kastler, Emmanuel J., et al., “Urodynamic Monitoring During Percutaneous Sacral Nerve Neurostimulation in Patients with Neurogenic Detrusor Hyperreflexia,” Neurourology and Urodynamics, pp. 61-71 (2001); Chartier-Kastler, Emmanuel J., et al., “Urodynamic Monitoring During Percutaneous Sacral Nerve Neurostimulation in Patients with Neurogenic Detrusor Hyperreflexia,” pp. 1476-1480 (2000); Kirkham, A.P.S., et al., “The Acute Effects of Continuous and Conditional Neuromodulation on the Bladder in Spinal Cord Injury,” Spinal Cord, pp. 420-428 (2001); Kirkham, A.P.S., et al., “Neuromodulation Through Sacral Nerve Roots 2 to 4 with a Finetech-Brindley Sacral Posterior and Anterior Root Stimulator,” pp. 272-281 (2002)).

[0087] With respect to the treatment of DSD, implantable sacral anterior root stimulators, such as the Brindley stimulator, were developed in the 1970s to restore bladder and bowel control for patients with SCI (see Brindley, G.S., “An Implant to Empty the Bladder or Close the Urethra,” J Neurol Neurosurg Psychiatry, pp. 358-369 (1977); Graham, H., et al., “An Implantable Neuroprosthesis for Restoring Bladder and Bowel Control to Patients With Spinal Cord Injuries: A Multi-Center Trial,” Archives of Physical Medicine and Rehabilitation (November 2001)). Such a system, referred to as the NeuroControl Vocare Bladder System, was FDA approved in 1998 under humanitarian designation. The NeuroControl Vocare Bladder System was the first and only system capable of treating DSD. However, to minimize unwanted results of stimulation, rhizotomy (a surgical operation to cut nerve roots) of the sacral nerve dorsal root was required when using this system. Due to the significant side-effects of such a radical surgical procedure, the therapy introduced its own side-effects and patho-physiologies, such as loss of sensation in the region controlled by the sacral nerve, such as the anus and buttocks, decreased bowel motility, loss of reflex erections and loss of reflex ejaculation in men, and vaginal dryness in women. These effects ultimately limited sales and the NeuroControl Vocare Bladder System is no longer marketed in the United States, leaving only catheterization, botulinum A toxin, and pharmacotherapy available to patients. Although these treatments make up the standard of care for SCI patients with neurogenic bladder, even when used in combination, they often fail to adequately restore normal bladder function.

[0088] One specific embodiment of a micturition management system that more effectively treats both DO and DSD in patients suffering from bladder dysfunction will now be described. Unlike traditional sacral nerve stimulation that effectively treats only DO, the micturition management system incorporates a pudendal nerve electrical stimulation and blocking regimen designed to control both sympathetic and parasympathetic branches of the autonomic nervous system, as well as aspects of the somatic nervous system, thereby enabling treatment of both DO and DSD in patients with neurogenic bladder, e.g., DO and DSD resulting from SCI. The micturition management system is specifically designed to modulate the pudendal nerve to provide both stimulation and blocking functions in different physiological and anatomical targets: the bladder and external urinary sphincter. To promote bladder filling, one channel of the micturition management system stimulates the pudendal nerve using a given set of neuromodulation parameters to help relax the bladder (detrusor) muscle. To void the bladder, the same channel of the micturition management system modulates the pudendal nerve with a different set of neuromodulation parameters to contract the bladder muscle. Concurrently, to keep the external urinary sphincter open to allow urine to be expelled, two other different independently controlled channels of the micturition management system block the external urinary sphincter. This concurrent blocking allows the external urinary sphincter to relax and allow urine to be expelled by the contracting bladder.

[0089] Thus, the micturition management system operates to improve both urine storage and voiding in patients with neurogenic bladder within the defined population by eliminating the need for catheterization, reducing episodes of incontinence and urinary tract infections (UTIs), increasing bladder capacity, improving urine flow, increasing voiding efficiency, and preventing vesicoureteral reflex, thereby improving kidney health. Thus, the micturition management system may restore normal urological function to patients with complete SCI who have lost voluntary bladder control by offering them the ability to voluntarily void at low pressures. The micturition management system also significantly reduces the burden on the patients’ family members, whom are often the primary care-givers in the management of neurogenic problems for those with SCI. Unlike previous interventions, which adversely affected the spinal reflex functions of the bowel and sexual organs, the micturition management system enables control of both autonomic and somatic nervous systems, and does not require sacral root rhizotomy. Thus, the micturition management system may preserve the spinal reflex functions of the bowel and sexual organs, and as such, will not compromise any existing nerve function in the region.

[0090] Significantly, elimination of undesirable action potential propagation between these three concurrently, yet independently activated, channels allow the micturition management system to function as intended. This elimination is achieved by appropriate electrical isolation of at least all but one of the concurrently modulated independent channels. This isolation for each such channel prevents the generation of undesirable action potentials in the neural network, especially between the channels of the implanted component of the micturition management system.

[0091] Referring to Fig. 1, an exemplary micturition management system 10 constructed in accordance with a generalized embodiment of the present inventions will now be described. The micturition management system 10 generally comprises three implantable neuromodulation lead assemblies 12 (12a-12c), an implantable pulse generator (IPG) 16, an external patient controller 18, a clinician’s programmer 20, and an external charger 22.

[0092] The IPG 16 may optionally be physically connected via lead extension(s) (not shown) to the neuromodulation lead assemblies 12. Fig. 2, the neuromodulation lead assemblies 12 are implantable leads, each of which includes an elongated lead body 24, an electrode assembly 26 (26a-26c) carried by the distal end of the respective lead body 24, and a proximal lead connector 28 (28a-28c) carried by the proximal end of the respective lead body 24.

[0093] Electrical neuromodulation energy (either electrical stimulation energy or electrical blocking energy), in the form of periodic electrical waveforms, may be between two (or more) activated electrodes of a given electrode assembly 26. Electrical neuromodulation energy may be transmitted to the tissue in multipolar manner (in this case, bipolar and bipolar) fashion. Bipolar neuromodulation occurs when two electrodes are activated as anode and cathode (for a given half-cycle) in an electrode assembly 26, so that electrical neuromodulation energy is transmitted between the electrodes in the electrode assembly 26. Tripolar neuromodulation occurs when three electrodes are activated in an electrode assembly 26, two as anodes and the remaining one as a cathode (for a given half-cycle), or two as cathodes and the remaining one as an anode (for a given half-cycle). As will be described in further detail below, electrodes in the electrode assembly 26a will deliver bipolar neuromodulation energy, whereas electrodes in each of the electrode assemblies 26b, 26bc will delivered tripolar neuromodulation energy.

[0094] As best shown in Figs. 2A and 2B, the IPG 16 comprises an outer case 30 for housing the electronic and other components (described in further detail below), and a header 32 containing three IPG connectors 34a-34c to which the proximal lead connectors 28 of the neuromodulation lead assemblies 12a- 12c respectively mate in a manner that electrically couples the electrode assemblies 26a-26c to the electronics within the outer case 30. The outer case 30 is composed of a biocompatible material, such as titanium, and forms a hermetically sealed compartment wherein the internal electronics are protected from the body tissue and fluids.

[0095] In one embodiment, each of the IPG connectors 34a-34c has very low resistant spring contacts (not shown) that allow for low insertion force. A series of O-ring seals (not shown) in each IPG connector 34 of the header 32 and, in the illustrated embodiment, epoxy in each proximal lead connector 28 prevent shorting or loss of signal. From each lead connector 28, a flexible connector (not shown) connects to each biocompatible metal electrode (not shown in Figs. 2A and 2B) in the respective electrode assembly 26. The set of conductors are each insulated from each other, and the entire set is insulated from body fluids with a plastic tube from the proximal end to the electrode assembly 26.

[0096] In the illustrated embodiment, each electrode assembly 26 takes the form of a cuff electrode assembly that goes around the target nerve (in this case, the pudendal nerve) and delivers the supplied electrical neuromodulation energy to the pudendal nerve. Each cuff electrode assembly 26 may comprise a rubber cuff that is split along one axis to allow placement around the pudendal nerve. The cable and cuff electrode assembly 26 are joined together to insure a reliable and low impedance electrical connection. Adhesive is applied to join the plastic insulation tube and cable to the rubber cuff. The cable may be looped to prevent stress at a laser weld to metal contacts of the electrodes of each respective cuff electrode assembly 26 and adhered with adhesive. Based on the variation of the pudendal nerve size and branching found in the intra-ligamentous space, several cuff sizes may be used to accommodate the ranges of pudendal nerves encountered in a patient. The three cuff electrode assemblies 26 may be any combination of sizes based on unique anatomical variations of the pudendal nerve and the implanting surgeon’s preference, partially based on estimation of nerve diameter size and neuromodulation testing that may be performed at the time of trial testing or implantation of the IPG

|0097] In the illustrated embodiment, the IPG 16 is fully implantable and self-contained inside the body of the patient for regular operation, including power provided typically by a battery and pulse generation circuitry (described in further detail below) that delivers the electrical neuromodulation energy in accordance with one or more predetermined tissue modulation regimens (or neuromodulation programs), which can be stored in the IPG 16, the external patient controller 18, and/or the clinician programmer 20. Each neuromodulation program defines the timing of the electrical waveforms concurrently delivered to the electrode assemblies 26a-26c respectively over independent channels (in this case, up to three electrical waveforms will be concurrently delivered to the three electrode assemblies 26a-26c (i.e., the three neuromodulation lead assemblies 12) over three independent channels), in addition to electrical pulse parameters defining the pulse amplitude, pulse duration, and pulse rate (or frequency) of each electrical waveform and their phase respective to each other. In an alternative embodiment, the power and control signals are transcutaneously delivered from an external controller across the skin to the IPG 16, which delivers the electrical neuromodulation energy in accordance with the control signals.

[0098] The external patient controller 18 may be used to telemetrically control the IPG 16 via a bi-directional RF communications link 36. Such control allows the IPG 16 to be turned on or off and to selectively activate different neuromodulation programs that have been previously stored in the IPG 16. The external patient controller 18 may also be used to modify a currently activated neuromodulation program in a limited manner to actively control the characteristics of the electrical neuromodulation energy output by the IPG 16, e.g., the amplitude.

[0099] The clinician programmer 20 provides clinician detailed neuromodulation parameters for programming the IPG 16 with one or more of the neuromodulation programs in the operating room and in follow-up sessions. The clinician programmer 20 may perform this function by indirectly communicating with the IPG 16, either directly or through the external patient controller 18, via an IR communications link 38, or alternatively a hardwired connection, Bluetooth, near field communication (NFC), etc. Alternatively, the clinician programmer 20 may directly communicate with the IPG 16 via an RF communications link (e.g., Medical Implant Communications Service (MICS) (not shown). The clinician detailed modulation parameters provided by the clinician programmer 20 are also used to program the external patient controller 18, so that the neuromodulation parameters can be subsequently modified by operation of the external patient controller 18 in a stand-alone mode (i.e., without the assistance of the clinician programmer 20).

[0100] The external charger 22 is a portable device used to transcutaneously charge the IPG 16 via an inductive link 40. Once its power source has been charged by the external charger 22 or otherwise replenished, the IPG 16 may normally function with either the external patient controller 18 or the clinician programmer 20 used for control.

[0101] For purposes of brevity, the details of the external patient controller 18, clinician programmer 20, and external charger 22 will not be described herein.

[0102] Referring now to Fig. 3, the main internal components of the IPG 16 will now be described. The IPG 16 comprises signal output circuitry 42 configured for generating electrical neuromodulation energy in accordance with defined electrical waveform having a specified pulse amplitude, pulse rate, and pulse width. In the illustrated embodiment, the signal output circuitry 42 comprises a plurality of independent signal generators 42a-42c corresponding to three independent channels CHI, CH2, and CH3 in which three electrical waveforms will be respectively delivered to the electrode assemblies 26a-26c (shown in Fig. 1). The neuromodulation energy generated by the signal generators 42a-42c of the signal output circuitry 42 is output to electrical terminals 44 corresponding to the proximal contacts on the IPG connectors 34a-34c (shown in Fig. 2A), and thus, contacts (described in further detail below) on the lead electrode assemblies 26a-26c. The neuromodulation energy may be output to the electrical terminals 44 via current limiting resistors and coupling capacitors (not shown) to ensure DC charge balance and patient safety.

[0103] In the illustrated embodiment, the signal output circuitry 42 comprises logic that can be programmed to generate neuromodulation energy in accordance with the programmed neuromodulation parameters. In particular, the signal generator 42a comprises one or more independently controlled current sources 45 for providing neuromodulation of a specified and known channel supply current to the corresponding lead electrode assembly 26a, while each of the signal generators 42b-42c comprises one or more independently controlled voltage sources 46 for providing neuromodulation of a specified and known channel supply voltage at the corresponding one of the lead electrode assemblies 26b-26c. However, in alternative embodiments, the signal generators 42a-42c may comprise any combination of independently controlled current sources and voltage sources. In the illustrated embodiment, the signal generator 42a for Channel CHI comprises a low range current source 45a (e.g., 0.05 mA to 1.2 ma), and a high range current source 45b (e.g., 1.15 mA to 10 mA), while each of the signal generators 42b-42c comprises a low range voltage source 46a (e.g., 0.3V to 2.5V) that delivers a low channel current, and a high range voltage source 46b (e.g., 2.35V to 12.9V) that delivers a higher channel current. Each of the signal generators 42a-42c also comprises a switch 48 for generating the waveform of the delivered neuromodulation energy in accordance with a defined frequency. Each of the low range current source 45a and high range current source 45b, and each of the low range voltage sources 46a and high range voltage sources 46b is variable (both timing and amplitude).

[0104] The amplitudes of the neuromodulation energy delivered through each channel may be varied by varying the low range current source 45a or the high range current source 45b (for Channel CHI) or the low range voltage source 46a or the high range voltage source 46b (for Channels CH2 and CH3), e.g., as controlled by the clinician programmer 20 (shown in Fig. 1). The clinician programmer 20 (shown in Fig. 1) is typically used to specify or program all of the modulation parameters, including pulse amplitude, pulse rate, and pulse width for the electrode assembly 26a, and pulse amplitude and pulse rate for assemblies 26b-26c, among other possible programmable features. In the illustrated embodiment, Channel CHI may be programmed with a biphasic, constant current pulsed waveform having an adjustable pulse amplitude in the range of 0.05 mA to 10 mA at a 50 pA step size and with a 10% tolerance; an adjustable pulse rate in the range of 1 Hz to 100 Hz at a 1 Hz step size and with a 0.5% tolerance; and an adjustable pulse width in the range of 120 ps to 1980 ps at a 60 ps step size with a 5% tolerance. Each of Channels CH2 and CH3 may be programmed with a biphasic waveform having a selectable amplitude in the range of 0.2 mA to 14 mA at a 0.05 mA step size and with a 10% tolerance; and an adjustable frequency in the range of 2 kHz to 20 kHz at a 0.5 kHz step size and with a 5% tolerance.

[0105] The IPG 16 further comprises monitoring circuitry 50 configured for monitoring the status of various nodes or other points 52 throughout the IPG 16, e.g., power supply voltages, temperature, battery voltage, and the like. The monitoring circuitry 50 may also be configured for measuring electrical parameter data associated with the electrode assemblies 26a-26c or other information from other sensors needed to determine the current activity level of the patient. The monitoring circuitry 50 is configured for directly measuring the delivered electrical current at the electrode assembly 26a, and measuring internal circuit parameters within signal output circuitry 42 for estimating the delivered electrical current to the electrode assemblies 26b-26c without directly measuring the delivered electrical current at these electrode assemblies 26b-26c. The monitoring circuitry 50 may optionally comprise an overcurrent protection circuit (not shown) that limits current to a safe value, e.g., less than 25 mA.

[0106] The IPG 16 further comprises power and control circuitry 54 that includes processing circuitry 56 (e.g., a microcontroller), a rechargeable power source 58, and power distribution circuitry 60. The processing circuitry 56 obtains status data from the monitoring circuitry 50 and independently controls the signal generators 42a-42c of the signal output circuitry 42 in accordance with the one or more neuromodulation programs stored in memory 62. The rechargeable power source 58 may, e.g., comprise a lithium-ion or lithium-ion polymer battery. The rechargeable power source 58 provides an unregulated voltage to the power distribution circuitry 60. The power distribution circuitry, in turn, generate the various voltages, some of which are regulated and some of which are not, as needed by the various circuits located within the IPG 16. The rechargeable power source 58 is recharged using rectified AC power (or DC power converted from AC power through other means, e.g., efficient AC-to-DC converter circuits, also known as “inverter circuits”) received from the external charger 22 (shown in Fig. 1), as discussed below.

[0107] The IPG 16 further comprises a charging coil 66 and associated charging circuitry 68, which may be contained in or applied to the outside of the outer case 30 of the IPG 16 (shown in Figs. 1 and 2). To recharge the power source 58, the external charger 22, which generates the AC magnetic field, is placed against, or otherwise adjacent, to the patient’s skin over the implanted IPG 16. The AC magnetic field emitted by the external charger induces AC currents in the charging coil 66. The charging circuitry 68 rectifies the AC current to produce DC current, which is used to charge the power source 58.

[0108] The IPG 16 further comprises a telemetry antenna 72 and associated telemetry circuitry 70, which may be contained within the header 32 of the IPG 16. The telemetry antenna 72 is configured for receiving communication data (e.g., control and/or programming data) from the external patient controller 18 and/or clinician programmer 20 (shown in Fig. 1) in an appropriate modulated carrier signal. The telemetry circuitry 70 is configured for demodulating the carrier signal it receives through the telemetry antenna 72 to recover the communication data. The telemetry circuitry 70 is further configured for relaying status data (e.g., data sensed through the monitoring circuitry 50) via the telemetry antenna 72 to the external patient controller 18 and/or clinician programmer 20.

[0109] While the IPG 16 is described as utilizing a dedicated charging coil for charging and dedicated telemetry antenna for bi-directional telemetry, it should be appreciated that the IPG 16 may alternatively utilize an AC receiving coil for receiving communication data and charging energy from the external devices, and an AC transmission coil for sending status data to the external devices.

[0110] Having described the structure and arrangement of the micturition management system 10, the mechanism of action/theory of operation of the micturition management system 10 for treating both DO and DSD in a patient with neurogenic bladder will now be described. Referring to Fig. 4, the micturition management system 10 electrically modulates the pudendal nerve PN in treating DO and DSD, and thus, effects both storage and voiding. Three sacral nerves (SI, S2, S3) bundle together to form the pudendal nerve PN. The pudendal nerve PN branches out to become the dorsal nerve DN, perineal nerve PEN, and inferior rectal nerve IRN.

[0111] Referring further to Fig. 5, the IPG 16 provides output to three independent channels (via the signal generators 42a-42c discussed above) by respectively energizing the three lead electrode assemblies 26a-26c around the common trunk of pudendal nerve PN. The lead electrode assemblies 26a-26c may be implanted on the common trunk of the pudendal nerve PN between the sacrotuberous and sacroiliac ligaments via a transgluteal approach and with the assistance of a cuff placement tool. As will be discussed in further detail below, the three independent channels include one bipolar channel (Bipolar Channel CHI associated with the lead electrode assembly 26a) and two tripolar channels (Tripolar Channel CH2 and Tripolar Channel CH3 respectively associated with the lead electrode assemblies 26b-26c). The lead electrode assembly 26a (Bipolar Channel CHI) and the lead electrode assembly 26b (Tripolar Channel CH2) are placed adjacent to one another on either the right pudendal nerve RPN or left pudendal nerve LPN, with the lead electrode assembly 26a placed centrally (peripherally to the lead electrode assembly 26b). The remaining lead electrode assembly 26c (Tripolar Channel CH3) is placed around the contralateral pudendal nerve.

[0112] As will be described in further detail below, during normal active operation of the micturition management system 10, Tripolar Channels CH2-CH3 may be activated with the same neuromodulation parameters between each other, but different from the neuromodulation parameters with which Bipolar Channel CHI will be activated. To ensure that the lead electrode assemblies 26a-26c are electrically coupled to the correct IPG connectors 34a-34c, the lead connector 28a associated with Bipolar Channel CHI is longer than the lead connectors 28b-28c associated with Tripolar Channels CH2-CH3, as illustrated in Fig. 2B, thereby ensuring that the lead connectors 28a-28c are respectively mated to the correct IPG connectors 34a-34c.

[0113] During normal active operation, the micturition management system 10 utilizes two primary modes, a Fill Mode, during which the bladder is relaxed to promote filling of the bladder B, and a Void Mode, during which contraction of the bladder B and relaxation of the external urinary sphincter EUS is synchronized to promote more efficient and effective voiding of the bladder B . [0114] During the Fill Mode, only the lead electrode assembly 26a associated with Bipolar Channel CHI is activated in a manner that stimulates the pudendal nerve PN at a relatively low frequency (e.g., less than 15 Hz, such as 5 Hz). The activation of Bipolar Channel CHI in this manner influences the bladder B in a manner that relaxes the detrusor muscle around the bladder B and inhibits spontaneous bladder contractions, thereby promoting greater filling and reducing episodes of incontinence. Though not fully elucidated, this mechanism is based on spinal interaction of somatic afferent fibers of the pudendal nerve PN with thoracolumbar sympathetic (hypogastric) and sacral parasympathetic (pelvic) systems controlling the bladder B that result in a strong inhibitory reflex that suppresses hyperreflexia (see Reitz, A., et al., “Afferent Fibers of the Pudendal Nerve Modulate Sympathetic Neurons Controlling the Bladder Neck,” Neurology and Urodynamics, pp. 597-601 (2003)). Furthermore, the activation of Bipolar Channel CHI in this manner provides direct pudendal efferent stimulation that maintains or enhances contraction and closure of the external urinary sphincter EUS, and may further enhance tone of the external urinary sphincter EUS.

[0115] Thus, , the frequency dependent interneuron modulation of the pudendal nerve PN via Bipolar Channel CHI influences the bladder B (in this case, relaxes the bladder B) via a neural pathway that includes the afferent pathway of the pudendal nerve PN and the efferent pathway of the hypogastric nerve via the spinal reflex of the sacral cord SC after SCI (between the lumbar cord LC and the brain BR), as well as influences the external urinary sphincter EUS (in this case, maintains contraction of the external urinary sphincter EUS) via a direct efferent pathway to the external urinary sphincter EUS.

[0116] During the Void Mode, the electrode assemblies 26a-26c associated with all three channels (i.e., Bipolar Channel CHI and Tripolar Channels CH2-CH3) are activated, so that the bladder B may contract and hence empty, and the external urinary sphincter EUS remains relaxed in order for urination to occur unimpeded from the bladder B. Relaxation of the external urinary sphincter EUS is essential to safely and effectively void when the bladder B contracts. In particular, the lead electrode assembly 26a associated with Bipolar Channel CHI is activated in a manner that stimulates the pudendal nerve PN at a relatively moderate frequency (e.g., greater than 15 Hz, such as 20 Hz to 30 Hz) and relatively low amplitude (e.g., typical 0.5mA (0.5V typical)), while the electrode assemblies 26b-26c respectively associated with Tripolar Channels CH2-CH3 are concurrently and independently activated at a relatively high frequency (e.g., in the range of 2-20 kHz) and relatively high amplitude (e.g., less than 15mA (typical 5V and 10 mA)) per channel in a manner that bilaterally and reversibly blocks the neuromodulation from Bipolar Channel CHI, as well as the natural efferent nerve signals from the central nervous system from contracting the external urinary sphincter EUS, thereby relaxing the external urinary sphincter EUS to allow it to open to permit low-pressure voiding of the bladder B. Initially, the lead electrode assembly 26a associated with Bipolar Channel CHI may be paused for a few seconds up to a minute while the electrode assemblies 26b-26c respectively associated with Tripolar Channels CH2-CH3 are activated to ensure that the external urinary sphincter EUS has been relaxed before attempting to void the bladder B.

[0117] Notably, relaxation of the external urethral sphincter EUS is important to safely and effectively void when the bladder B contracts. Block of the external urethral sphincter EUS contraction by high frequency, biphasic neuromodulation has been shown to be a non-synaptic phenomenon due to a block of pudendal efferent conduction, rather than to external urethral sphincter EUS fatigue. The mechanism of action has been explored by others through published modeling studies and is postulated to result from altered sodium channel dynamics due to membrane depolarization or diminished action potential amplitudes due to large potassium currents (see Bhadra, N., et al., “Simulation of High-Frequency Sinusoidal Electrical Block of Mammalian Myelinated Axons,” J Comput Neurosci, pp. 313-326 (2007); Williamson, R.P., et al., “Localized Electrical Nerve Blocking,” IEEE Transactions on Biomedical Engineering,” pp. 362-370 (2005); Tai, C., et al., “Simulation of Nerve Block by High-Frequency Sinusoidal Electrical Current Based on the Hodgkin-Huxley Model,” IEEE Transactions on Neural Systems and Rehabilitation Engineering, pp. 414-422 (2005)). Additionally, efferent nerve block remains effective over long periods of time as opposed to methods inducing fatigue, which lose effectiveness over time as the muscle adapts (see Tai, C., et al., “Responses of External Urethral Sphincter to High Frequency Biphasic Electrical Stimulation of Pudendal Nerve,” Journal of Urology, pp. 782-786 (2005); Schmidt, Richard A., “Neural Prostheses and Bladder Control,” Engineering in Medicine and Biology Magazine, pp. 31-36 (June 1983)). Once the external urethral sphincter EUS is successfully blocked, resumed stimulation of Bipolar Channel CHI at a moderate frequency (20 Hz) results in excitation of the detrusors and bladder emptying. [0118] Again, the exact mechanism has not been fully elucidated; although spinal interaction between afferent pudendal PDN fibers and the pelvic nerve PN are probably required (see Tai C., “Inhibitory and Excitatory Perigenital-to-Bladder Spinal Reflexes in the Cat,” American Journal of Physiology - Renal Physiology, pp. F591-F602 (2008). Empirical data indicate that the neuromodulation currents for excitation are similar to that for inhibition; however, stimulation frequencies differ. One possible explanation for the observed difference in outcomes is that the afferent firing at different frequencies might trigger release of different neurotransmitters at the first spinal synapse between primary afferent axons and spinal interneurons resulting in either an inhibitory or excitatory effect on bladder activity (see Wang J., et al., “Bladder Inhibition or Excitation by Electrical Perianal Stimulation in a Cat Model of Chronic Spinal Cord Injury,” British Journal of Urology International, pp. 530-536 (2009).

[0119] Thus, as illustrated in Fig. 6, the stimulation of the pudendal nerve PN via Bipolar Channel CHI influences the bladder B (in this case, contracts the bladder B) via a neural pathway that includes the afferent pathway (shown as dotted line) of the pudendal nerve PN and the efferent pathway (shown as solid line) of the pelvic nerve PN via the spinal reflex of the sacral cord SC, while modulation of the pudendal nerve PN via Tripolar Channels CH2-CH3 blocks the direct efferent pathway (shown as solid line with X’s) to the external urinary sphincter EUS, thereby preventing Bipolar Channel CHI and natural neural tone from influencing the external urinary sphincter EUS (in this case, preventing the external urinary sphincter EUS from contracting).

[0120] Referring to Fig. 7, one exemplary neuromodulation sequence performed by the micturition management system 10 will be described. In this exemplary neuromodulation sequence, the Fill Mode and Void Mode are cycled approximately 5-6 times per day, with the duration of the Fill Mode being relatively long, while the duration of the Void Mode being relatively short. At the beginning of the Fill Mode, Bipolar Channel CHI may be paused (e.g., up to two hours) for a period defined by “Delay 1” to conserve battery power, since inhibition of bladder activity is not required until the bladder B is partially filled. During the remainder of the Fill Mode, Bipolar Channel CHI is activated (e.g., in the range of l-10Hz) to inhibit bladder activity. At the beginning of the Void Mode, Bipolar Channel CHI is paused again (e.g., approximately in the range of 5 to 60 seconds) for a period defined by “Delay 2,” while Tripolar Channels CH2-CH3 are activated (e.g., from 6-10kHz) to relax the external urinary sphincter EUS. During the remainder of the Void Mode, Bipolar Channel CHI is activated (e.g., in the range of 20-40Hz) to exhibit bladder activity, while Tripolar Channels CH2-CH3 remain activated to continue to relax the external urinary sphincter EUS.

[0121] One important goal when designing an electrical neuromodulation system is to minimize neuromodulation current for maximum power efficiency, while eliciting desired reaction to the delivered neuro-modulation, while also minimizing nerve damage and undesirable physiological side-effects. To this end, the micturition management system 10 is specifically designed to eliminate or minimize leakage within and cross-talk between the Bipolar Channel CHI and Tripolar Channels CH2-CH3 by appropriate channel isolation. For the purposes of this specification, the term “leakage” denotes the presence of unwanted current from a single electrical circuit, while the term “cross-talk” refers to its commonly accepted definition: in electronics, cross-talk is any phenomenon by which a signal transmitted on one circuit or channel of a transmission system creates an undesired effect in another circuit or channel. Cross-talk is usually caused by undesired capacitive, inductive, or conductive coupling from one circuit or channel to another.

[0122] Significantly, because the micturition management system 10 concurrently activates Bipolar Channel CHI and Tripolar Channels CH2-CH3 during the Void Mode, significant cross-talk between these channels may inadvertently cause an undesirable effect, as illustrated in Fig. 8. Such cross-talk may cause problems with incomplete blocking, i.e., generating an undesirable action potential in the pudendal nerve PN. In particular, it is possible that the high current (blocking) Tripolar Channels CH2-CH3 may mask the low current Bipolar Channel CHI through a cross-talk signal, interfering with bladder contraction. Also, if Tripolar Channels CH2-CH3 are operating at different frequencies or the same frequency, but different phase, the cross-talk between these two channels may increase or reduce the neuromodulation current, causing an undesirable result, such as over- or under-stimulation of the pudendal nerve PN or unintended stimulation and effects on other nerves. Thus, a cross-talk signal may be generated between the channels that can cause the external urethral sphincter EUS to contract even if Tripolar Channels CH2-CH3 block the pudendal nerve PN. [0123] The nature of cross-talk will depend on the approaches for delivering electrical neuromodulation to the target nerve (e.g., transdermal, percutaneous, transcutaneous, and fully implantable). Each approach requires access to the target nerve that is obtained in different ways and can either have external sources of power or signal generation or internal (to the body) sources of power and/or signal generation.

[0124] In transdermal neuromodulation, the target nerves are accessed by providing the neuromodulation signal on the surface of the skin, without any physical penetration of the skin. This approach relies on passive transmission and conduction of the electrical signal to the target nerves along whatever neural pathways are available. As it is not targeted to a specific nerve, but to an area of the skin, which is then expected to modulate the nerve(s) of interest, this technique may be useful to resolve a local issue, such as localized pain using Transcutaneous Electrical Nerve Stimulation (TENS) (see Johnson, Mark, “Reviews in Pain” (2007)).

[0125] In percutaneous neuromodulation, the target nerves are accessed by mechanical penetration through the skin with electrodes that are typically needle-shaped for ease of penetration into or through the skin while minimizing pain, with external power and signal generation source(s) that deliver the neuromodulation energy. This source or multiple sources can be wearable, typically on the skin in the form of a patch, stocking or integrated into clothing. They can also be non-wearable- either portable or not. If portable, then the user can carry the power source/signal generation electronics. The power can be derived from batteries or from the mains, with some form of electronics to generate the neuromodulation signal and directly connect to the delivery electrodes assemblies. One such example of a percutaneous electrical neuromodulation system is PTNS (Percutaneous Tibial Nerve Stimulation) for applications such as Over-Active Bladder (OAB) (see Wang, Menghua, et al., “Percutaneous Tibial Nerve Stimulation for Overactive Bladder Syndrome: A Systematic Review and Meta-Analysis,” International Urogynecology Journal, pp. 2457-2471 (December 2020).

[0126] In transcutaneous neuromodulation, there are not just the electrodes and leads that are implanted in the body, but also some electronics with no through-the-skin components. The power to these implanted electronics is provided across the skin, using wireless transmission. In some cases, the signal as well as the power can be coupled across the skin and transmitted through the skin to the coupling electronics on the inside, which then condition and transmit the signal to the implanted electrodes that conduct it to the target nerves.

[0127] In fully implantable neuromodulation, the implantables are self-contained, in that there is an IPG inside the body that has its own source of power and electrical signal generation circuity that can internally generate the neuromodulation signals required, either by getting an appropriate command from outside the body or self-generating this signal based on internal firmware programming. The IPG’s internal electronics then transmit the signal to the implanted electrodes that conduct it to the target nerves via leads.

[0128] For any of the neuromodulation approaches discussed above, the minimum number of channels required to neuromodulate one target nerve of interest is one. Even in this case, there is the potential for undesirable interference from the delivered electrical energy. Typically, in this case, and that has been common amongst neuromodulators developed to date, the focus is on minimizing the leakage of delivered energy along the entire single-channel delivery path: from the power source to the pulse generator to the connecters, leads, and ultimately electrodes that are in contact with the selected target nerve.

[0129] Referring to Fig. 9, leakage with respect to a conventional single-channel neuromodulation system 100 will first be described. The neuromodulation system 100 comprises a power source 102 that interacts with the human body 110 to which it is supplying electrical neuromodulation via a bipolar electrode assembly 104. The power source 102 may be outside the human body 110 in the case of transdermal neuromodulation or percutaneous neuromodulation, or may be inside the human body 110 in the case of transcutaneous neuromodulation or fully implantable neuromodulation. The power source 102 is shown as having only one channel (Channel CHx) that is energized at a representative voltage of 0.1V at an active terminal 106. The bipolar electrode assembly 104 completes the electrical circuit in this case, with a resistance shown depicting the impedance between the two electrodes 104a, 104b that form the bipolar electrode assembly 104. The electrical current in this case completes the electrical circuit by passing through this complete circuit, starting from an active terminal 106 and returning to a ground terminal 108 inside the power source 102. [0130] In this case, even in the presence of several alternative electrical paths, the delivered electrical energy has minimal cross-talk as there are limited undesirable electrical paths for the delivered energy. This holds if the entire modulation delivery loop, from the electronics of the power source 102 to the wires (leads) that go to the target nerve and the bipolar electrode 104 itself, are designed to minimize electrical leakage and restrict the delivered neuromodulation to follow the desired path around this circuit. Thus, in the case of a single-channel neuromodulation system, there may be a challenge of leakage, but not of cross-talk.

[0131] Instead of a bipolar electrode configuration, if only a unipolar electrode were used to deliver neuromodulation from the power source 102, the return path for the delivered neuromodulation to the power source 102 (the electrical “ground” in this case) would be through body tissue and some part of the physiological neural network, which can also cause secondary stimulation and undesirable side-effects. As a result, even in the case of a single channel neuromodulator, it is important to use at least bipolar electrodes when delivering neuromodulation to keep that channel’s neuromodulation energy from ‘leaking out’ and causing undesirable side-effects.

[0132] In the case of transdermal neuromodulation, mechanical means of minimizing leakage become as important as electrical means. Careful electrode design and tissue contact of the external electrodes to the skin influences how the delivered electrical energy at the surface of the skin dissipates inside the body, gets to the nerves and tissues of interest, and then returns back safely without causing undesirable effects. In the transdermal neuromodulation approach, there is such broad dispersion of the electrical neuromodulation inside the body that it is inherently impossible to eliminate leakage, even for a single channel transdermal neuromodulation system. This leakage problem also holds for a multi-channel transdermal neuromodulation system, even if the channels are sequentially modulated. For a transdermal neuromodulation system requiring concurrent independent neuromodulation, the problem of cross-talk is exacerbated even further due to the wide-spread and unfocused delivery of neuromodulation energy.

[0133] In the case of percutaneous neuromodulation systems, mechanical means of minimizing leakage and undesirable cross-talk are important. Since energy is being transmitted to the target nerve using through-the-skin techniques, electrical means of minimizing cross-talk do come into play as there is now directed neuromodulation to specific parts of the nervous system, which can interact with each other if leakage and cross-talk are not considered.

[0134] Even in this case, careful electrode design and tissue contact of the external electrodes to the intended target inside the body influences how the delivered electrical energy, at the selected anatomical location, dissipates when delivered to the nerves and tissues of interest, and then returns back safely without causing undesirable effects. This becomes especially relevant if there is only one active element of a channel in contact with the target nerve and the return path of the delivered neuromodulation is dissipated throughout the body. This might lead to undesirable side-effects. Even for a nerve target being modulated with a pair of electrodes to complete the electrical circuit back to the activating electronics outside the body, there could be an issue of leakage and cross-talk in the case of multiple independent channels being concurrently activated.

[0135] Challenges with leakage and cross-talk also exist for transcutaneous neuromodulation systems. In particular, and with reference first to Fig. 10, leakage and crosstalk with respect to a conventional multi-channel transcutaneous neuromodulation system 120 will be described. The transcutaneous neuromodulation system 120 comprises a single external power source 122 with a single drive coil and a single passive receiver-neuromodulator 124 with a single power coil. The external power source 122 inductively transmits power through a skin barrier 112 of the human body 110 to the receiver-neuromodulator 124 without any intervening electronics (signal processing or signal conditioning) in the receiver-neuromodulator 124. The receiver-neuromodulator 124 contains one or more power couplings (not shown) that captures the external transmitted power and concurrently directs it as electrical neuromodulation signals to the appropriate nerve or nerves over two channels (Channel CHx and Channel CHy) via bipolar electrode assemblies 126. The neuromodulation signals for respective Channels CHx and CHy are not independently controlled, and thus, have the same neuromodulation parameters. Each bipolar electrode assembly 126 of a respective channel completes the electrical circuit, with a resistance shown depicting the impedance between the two electrodes 126a, 126b that form the bipolar electrode assembly 126. For each of Channels CHx and CHy, the electrical current in this case completes the electrical circuit by passing through this complete circuit, starting from an active terminal 128 and returning to a ground terminal 130 inside the receiver-neuromodulator 124. In this case, the ground between the two channels (Channels CHx and CHy) is shared (either by using the same ground terminal 130 or electrically coupling the ground terminals 130 together). As such, there will be electrical cross-talk between concurrently activated Channels CHx and CHy via the representative cross-talk pathway 132, with a resistance shown depicting the impedance in the cross-talk pathway 132.

[0136] With reference first to Fig. 11, leakage and cross-talk with respect to another conventional multi-channel transcutaneous neuromodulation system 140 will be described. In this case, rather than a passive receiver-neuromodulator, an IPG with active electronics is implanted within the human body 110. In particular, the transcutaneous neuromodulation system 140 comprises a single IPG 142 with a receiver 146 and a single external power source 144. The external power source 144 inductively transmits power and control signals through a skin barrier of the human body 112 to the receiver 146 of the IPG 142, which utilizes the power and control signals to concurrently and independently generate and apply neuromodulation signals to the appropriate nerve or nerves over two channels (Channels CHx and CHy) via bipolar electrode assemblies 148. Because the neuromodulation signals for respective Channels CHx and CHy are independently controlled, they may have different neuromodulation parameters VI and V2. Each bipolar electrode 148 of a respective channel completes the electrical circuit, with a resistance shown depicting the impedance between the two contact electrodes 148a, 148b that form the bipolar electrode assembly 148. For each of Channels CHx and CHy, the electrical current in this case completes the electrical circuit by passing through this complete circuit, starting from an active terminal 150 and returning to a ground terminal 152 inside the IPG 142. In this case, the ground between the two channels (Channels CHx and CHy) is shared (either by using the same ground terminal 152 or electrically coupling the ground terminals 152 together), and thus, there will be electrical cross-talk between concurrently activated Channels CHx and CHy via the representative cross-talk pathway 154, with a resistance shown depicting the impedance in the cross-talk pathway 154.

[0137] With reference first to Fig. 12, leakage and cross-talk with respect to a conventional multi-channel fully implantable neuromodulation system 160 will be described. The fully implantable neuromodulation system 160 comprises an IPG 162 containing its own power source (not shown) and internal circuitry for generating and applying neuromodulation signals to the appropriate nerve or nerves over two channels (Channels CHx and CHy) via bipolar electrode assemblies 164. Each bipolar electrode assembly 164 of a respective channel completes the electrical circuit, with a resistance shown depicting the impedance between the two contact electrodes 164a, 164b that form the bipolar electrode assembly 164. For each of Channels CHx and CHy, the electrical current in this case completes the electrical circuit by passing through this complete circuit, starting from an active terminal 166 and returning to a ground terminal 168 inside the IPG 162. In this case, the ground between the two channels (Channels CHx and CHy) is shared (either by using the same ground terminal 168 or electrically coupling the ground terminals 168 together), and thus, there may possibly be electrical cross-talk between Channels CHx and CHy via the representative cross-talk pathway 170, with a resistance shown depicting the impedance in the cross-talk pathway 170.

[0138] The challenges posed by both leakage and cross-talk in the fully implantable neuromodulation system 160 can be significant due to the smaller, compact footprint of the IPG 162, the reliance on power and signals from inside the IPG 162 for normal operation, resulting in power and signal generating electronics confined to a small, self-contained package that must be reliable, minimizing power consumption to reduce size of the implantable battery (either primary or rechargeable), generate as little heat as possible to prevent tissue damage from thermal dissipation, and increase the time between charging, and the charging time, for a re-chargeable battery or increase the time between replacement of a non-rechargeable battery. Furthermore, due to the close proximity of the channels within the smaller, more compact, footprint of the IPG 162, signals must be generated in closer electrical proximity to each other, cross-talk between the channels is more difficult to eliminate.

[0139] If the IPG 162 sequentially delivers neuromodulation on each of Channels CHx and CHy, then, as long as the inactive channel is switched off when not active, electrical crosstalk between Channels CHx and CHy will not be present. This is shown in Fig. 13, where one channel (in this case, Channel CHx) is active and the other channel (in this case, Channel CHy) is inactive, such that Channel CHx is grounded to the same ground as Channel CHy. In this case, no cross-talk between Channels CHx and CHy is present even though there is a cross-talk pathway in the body between Channels CHx and CHy. [0140] As illustrated in Fig. 14, if the IPG 162 concurrently delivers neuromodulation energy with the same neuromodulation parameters (e.g., same amplitude, frequency, width, and phase) on Channels CHx and CHy, leakage exists between Channels CHx and CHy and undesired action potentials may be generated as a result of the potential cross-talk between Channels CHx and CHy. However, the leakage current between Channels CHx and CHy across the cross-talk pathway 170 will be minimal as electrical current in Channels CHx and CHy will prefer to be confined to their own return path instead of selecting to cross over to the other channel’s return path and create undesirable effects.

[0141] It is possible for neuromodulation systems to use this approach and still have the system function as intended without material side-effects. However, over time, the circuit parameters in each channel may change differently due to different material degradation in the leads and electrodes, different neural and physiological changes in one channel’s pathway compared to the other, which might result in different circuit impedances and that difference may be enough to cause a significant cross-talk current between these two channels leading to undesirable side-effects. This potential change in impedances is certainly important for constant current neuromodulation, while it matters but less so for constant voltage neuromodulation. Furthermore, when the neuromodulation system is used to modulate two different nerves for different effects, the neuromodulation parameters of channels may differ from each other. Thus, in some instances, it may not be optimal for a multi-channel neuromodulation system to deliver energy with the same neuromodulation parameters.

[0142] Fully implantable multi-channel neuromodulation systems typically have not required the functionality of concurrent activation of the channels with different neuromodulation parameters. As described with respect to Figs. 13 and 14 above, fully implantable multi-channel neuromodulation systems have traditionally activated just one channel at a time or have activated multiple channels with the same signal at the same time. Concurrently activated, multiple independent channels with different neuromodulation parameters have not been advanced beyond acute in vivo studies. Since external, independent power and signal generation electronics are utilized in such cases, then the problem of cross-talk between the concurrently activated, multiple independent channels does not usually manifest itself. [0143] Acute testing performed and reported by others is with external neuromodulation that can be relatively easily isolated outside the body. This is not the case with an implantable device, an issue whose implementation has been ignored by researchers and developers as they have not progressed to chronic implanted use with efficacious results.

[0144] As illustrated in Fig. 15, if the IPG 162 concurrently delivers neuromodulation with the different neuromodulation parameters on Channels CHx and CHy, and in the illustrated embodiment, different amplitudes (0.1V on Channel CHx and 5V on Channel CHy), cross-talk between the two channels may interfere with each other and may cause undesirable physiological effects. As noted earlier, differences in neuromodulation parameters can be not just in amplitude, but in frequency and phase as well.

[0145] In summary, there are significant challenges to overcome for neuromodulation systems with respect to leakage and cross-talk. For a single-channel neuromodulation system, there is the potential for leakage of the supplied neuromodulation within the single-channel circuit. If the leakage is excessive, it can cause undesirable physiological effects. For a multichannel neuromodulation system, the leakage problem from within any channel remains. In addition, there is the potential problem caused by cross-talk between any two channels. This latter problem is especially acute in the case of at least two independent channels of a multichannel neuromodulator being activated concurrently and with different neuromodulation parameters. These challenges are typically faced by percutaneous, transcutaneous or fully implantable neuromodulation systems.

[0146] It is possible to electrically isolate Channels CHx and CHy by utilizing two separate IPGs to concurrently deliver neuromodulation energy through independent Channels CHx and CHy. However, the IPGs would need to communicate with each other to coordinate the delivery of the neuromodulation energy through Channels CHx and CHy. Furthermore, each IPG must not share or have a common ground, and thus, the internal electronics must float and be isolated from the outer casings of the IPGs by not having their electrical grounds tied to the outer casings of the IPGs. Lastly, the use of multiple IPGs would significantly increase the cost of the fully implantable neuromodulation system. As such, the use of multiple IPGs to concurrently deliver neuromodulation energy through independent channels is impractical. [0147] It is also possible to electrically isolate Channels CHx and CHy by utilizing a single IPG, but powering each channel with its own independent power battery with no electrical connection between the separate circuits, including ground even to the outer casing of the IPG. This would achieve isolation of Channels CHx and CHy from each other, but at the cost of additional hardware, including microprocessors, and power conditioning and battery recharging circuitry. Furthermore, the microprocessors would still need to communicate with each other to coordinate the delivery of the neuromodulation energy through Channels CHx and CHy. As such, the multiplication of power and control circuitry in an IPG to concurrently deliver neuromodulation energy through independent channels is impractical.

[0148] The inventors have developed several approaches to overcome these challenges without requiring multiple IPGs or multiplication of power and control circuitry.

[0149] Several approaches used by the micturition management system 10 to mechanically limit the leakage of delivered neuromodulation within a channel, and in particular, to limit the leakage of the delivered neuromodulation from within each of Bipolar Channel CHI and Tripolar Channels CH2-CH3, will be described in further detail below. These means of mechanically limiting the leakage can be used either separately or together to achieve these objectives of a well-functioning neuromodulation system that is safe, effective and easy to use by the recipient. The ease-of-use is achieved by minimizing the neuromodulation current required to achieve the desired function, which in turn improves IPG battery life, which for a given battery power-handling capacity leads to a smaller and lighter implantable battery or similar power source, and/or it increases the intervals/ reduces the time to recharge the implantable battery or power source if it is rechargeable. If not rechargeable, minimizing power draw increases the life of the non-rechargeable power source and increases the interval between replacement of the IPG or the non-rechargeable power source.

[0150] Mechanical isolation of electrical charge delivery to the nerve is critically important to prevent unwanted stimulation of nerves/tissue. This starts with electrical charge delivery from the IPG 16 to the intended therapy site (in this case, the pudendal nerve PN), through the neuromodulation lead assemblies 12a- 12c even for a single channel. [0151] Each of the lead electrode assembly 26 is cuff-shaped for larger coverage of cross-section of the pudendal nerve PN (as illustrated in Fig. 16A) compared to side electrode assembly 26’ that can be attached parallel to the pudendal nerve PN (as illustrated in Fig. 16B). Accurate coverage (i.e., good electrode-to-nerve contact and coverage along the circumference of the nerve) prevents side effects, such as inadvertent stimulation of surrounding muscle and nerves, e.g., the gluteal and adductor muscles and related nerves. The cuff design of the lead electrode assemblies 26a-26c allows neuromodulation energy to fully penetrate the pudendal nerve PN, and with respect to the lead electrode assemblies 26b-26c during the Void Mode, enabling blocking of the pudendal nerve PN.

[0152] Mechanical isolation of electrical charge delivery can be improved by selecting the configuration and design of the neuromodulation lead assemblies 12a- 12c in accordance with how action potentials are conducted on myelinated nerves, such as the pudendal nerve PN, which utilize Nodes of Ranvier to increase conduction velocity of action potential propagation, as illustrated in Figs. 17 and 18. Notably, depolarization and action potential only occur in the nodes, with passive conduction of depolarization occurring from node to node. By “jumping” from node to node, transmission is faster.

[0153] The key dimensions to consider when designing a set of electrodes, and their assemblies, is to achieve the desired function: transmission or blocking is determined in part by the nerve dimensions, and in particular by a) distance between adjacent Nodes of Ranvier (Y) and b) nerve diameter (X), as illustrated in Fig. 18. From a physiological standpoint, it has been established that dimensionally the distance between adjacent Nodes of Ranvier (the inter-nodal distance Y) of a nerve is equal to the nerve diameter (X). In accordance with this physiological nerve ratio, different sizes of the cuff designs (e.g., four different sizes) of the lead electrode assemblies 26a-26c are designed to accommodate the variation in diameter of the pudendal nerve PN expected to be encountered clinically. These different cuff designs not only cater to a specific range of diameters of the pudendal nerve PN, but also determine the geometry and spacing of the contacts of the lead electrode assemblies 26a-26c used to prove either stimulation or blocking of the pudendal nerve PN of a particular diameter along the length of the pudendal nerve PN, as will be described in further detail below. [0154] In general, the lead electrode assemblies 26b-26c encircle the pudendal nerve PN with a thick layer of insulation to confine and focus the neuromodulation energy from the contacts onto the outer surface of the pudendal nerve PN. Each lead electrode assembly 26 comprises a cuff body 80 composed of a biocompatible insulator material (e.g., silicone rubber), and co-radial contact electrodes 82 (e.g., circumferential flattened metallic wire (e.g., platinum) electrodes) affixed to the inner surface of the cuff body 80 for current flow, as illustrated in Figs. 19A-19B. In the illustrated embodiment, the width (along the axis of the pudendal nerve PN) of each contact electrode 82 is 0.5mm, although other values are contemplated. The insulation of the cuff body 80 assures that the delivered electrical charge is confined to the surfaces of the contact electrodes 82, which are in direct contact with the pudendal nerve PN, so that just the pudendal nerve PN is modulated with electrical charge, and leakage of electrical current to nontargeted tissue is minimized. In the illustrated embodiment, the spacing between adjacent contact electrodes 82 is 2.5mm, the spacing between adjacent contact electrodes 82 may vary to correspond with Nodes of Ranvier and intemodal length that is optimized for maximal conduction velocity (see Salzer J.L, “Clustering Sodium Channels at the Node of Ranvier: Close Encounters of the Axon-Glia Kind,” Neuron, pp. 843-846 (1987). It is preferred to have a slight spring closure of the cuff body 80 to maintain firm contact between the contact electrodes 82 and the pudendal nerve PN for better electrical charge coupling. Each lead electrode assembly 26 may include means (not shown) for tightening the cuff body 80 circumferentially around the pudendal nerve PN. Such means can include sutures embedded inside the cuff body 80 and/or a spring clip used to snugly fit the cuff body 80 and subsequently the lead electrode assembly 26 around the pudendal nerve PN.

[0155] The contact electrodes 82 of each lead electrode assembly 26 are configured for being placed around approximately seventy-five percent of the circumference of the pudendal nerve PN, as illustrated in Fig. 16A. In the illustrated embodiment, the dimension of cuff body 80 that corresponds with the circumference of the pudendal nerve PN is 7.9mm, although other values are contemplated. In the case of the lead electrodes assemblies 26b-26c (Tripolar Channels CH2-CH3), the circumferential configuration of the contact electrodes 82 is conducive to enable nerve blocking of the entire nerve bundle. In the case of the lead electrode assembly 26a (Bipolar Channel CHI), a side electrode assembly 26’ with circumferentially disposed contacts or a linear cuff (not shown) with linearly disposed contacts could alternatively be used for neuromodulation, since the neuromodulation energy need not be confined within the span of the lead electrode assembly 26a. While the side electrode assembly 26’ or linear cuff may be suitable for neuromodulation given electrically sound and reliable contact long-term with the pudendal nerve PN, with their limited and unreliable coverage of the cross-section of the pudendal nerve PN, these electrode and assembly configurations will be much more inefficient for providing blocking functions.

[0156] The lead electrode assembly 26a for enabling the neuromodulating function of Bipolar Channel CHI (to relax the bladder B during the Fill Mode or contract the bladder B during the Void Mode) is designed and implemented in a bipolar configuration. In particular, the lead electrode assembly 26a takes the form of a bipolar nerve cuff electrode assembly, and thus, two contact electrodes 82a, 82b are affixed to the inner surface of the cuff body 80, as illustrated in Fig. 19A, with one of the contact electrodes 82a, 82b (e.g., the contact electrode 82a) serving as a “cathode” and the other of the contact electrodes 82a, 82b (e.g., the contact electrode 82b) serving as an “anode.”

[0157] The intent of Bipolar Channel CHI is to transmit the neuromodulation along the length of the pudendal nerve PN non-preferentially in both directions of the nerve bundle (bidirectional stimulation for activating both the bladder B and the external urinary sphincter EUS), as illustrated in Fig. 20. To this end, the spacing between the contact electrodes 82a, 82b of the lead electrode assembly 26a is such that the contact electrodes 82a, 82b respectively overlap at least one Node of Ranvier.

[0158] As illustrated in Figs. 21A-21B, activation of the contact electrodes 82a, 82b of the lead electrode assembly 26a creates an electrical field (shown by field lines) between the contact electrodes 82a, 82b that depolarizes the membrane of the pudendal nerve PN, thereby generating an action potential. The field lines shown in Figs. 21A-21B are only representative of the electrical field between the contact electrodes 82a, 82b. In reality, the electrical field between the contact electrodes 82a, 82b will have many more field lines. For example, although the field lines of the electrical field are only shown in Fig. 2 IB on the top half of the contact electrodes 82a, 82b for purposes of brevity, the field lines of the electrical field will also exist on the bottom half of the contact electrodes 82a, 82b. Under physiological conditions, an action potential in the pudendal nerve PN is generated at one end of an axon, and proceeds towards the other end of the axon. Generally, an electrical pulse will cause nerve stimulation along both directions of the nerve. In particular, when a nerve is artificially stimulated as in the case of neurostimulation, two propagating action potentials, one in the orthodromic direction (towards the terminal end of the axon where the neurotransmitter is released) and one propagating in the antidromic direction (towards the soma of the axon), are created, as illustrated in Fig. 20. Furthermore, the respective polarizations of the contact electrodes 82a-82b are only illustrated in Fig. 2 IB during one half cycle of the neuromodulation energy provided to the electrodes 82a- 82b. Thus, for one half cycle, the contact electrodes 82a-82eb will have a particular polarization (in the illustrated case, the contact electrodes 82b has a positive polarization, and the contact electrode 82a has a negative polarization), and in the other half cycle, the polarization of the contact electrodes 82a-82b will reverse to provide charge balance via biphasic delivery of the neuromodulation energy.

[0159] The lead electrode assemblies 26b-26c for enabling the blocking function of Tripolar Channels CH2-CH3 (to prevent action potentials, either naturally occurring or generated by Bipolar Channel CHI stimulation from inducing contraction and closure of the EUS during the Void Mode) take the form of tripolar nerve cuff electrode assemblies, and thus, three contact electrodes 82c-82e are affixed to the inner surface of the cuff body 80 for current flow, as illustrated in Fig. 19B. Each of the lead electrode assemblies 26b-26c has a central “cathode” (inner contact electrode 82d) flanked by a pair of “anodes (outer contact electrodes82c, 82e), thereby dividing the total current of the “cathode” between these two “anodes.” The outer contact electrodes82c, 82e are connected together with a conductor (not shown) and deliver electrical charge with respect to the inner contact electrode 82d. Since there is current flowing to both anodes, the potential at each end of the tripolar nerve cuff electrode assembly is similar, and there is a reduced tendency for current to flow outside the cuff geometry, ensuring that most of the current is contained within the walls of the tripolar nerve cuff electrode assembly, thereby creating a self-contained blocking field. Because the insulation of the cuff body 80 confines the electrical charge to the inside of each lead electrode assembly 26b, 26c, essentially, no charge leaves the inside of the respective lead electrode assembly 26b, 26c. It is important to have an appropriately sized cuff body 80 of the respective lead electrode assembly 26b, 26c to fit the pudendal nerve PN, so that the cuff body 80 closes and leaves no gap for electrical charge to escape and modulate tissue outside the cuff body 80.

[0160] The intent of Tripolar Channels CH2-CH3 is to prevent the neuromodulation along the length of the pudendal nerve PN non-preferentially in both directions of the nerve bundle, as illustrated in Fig. 22. To this end, the spacing between the contact electrodes 82c-82e of each lead electrode assembly 26b, 26c is such that the contact electrodes 82c-82e span at least one Node of Ranvier to block saltatory conduction along the length of the pudendal nerve PN.

[0161] As illustrated in Figs. 23A-23B, activation of the contact electrodes 82c-82e of the lead electrode assembly 26a creates an electrical field between the contact electrodes 82c, 82d and an electrical field between the contact electrodes 82d, 82e that depolarize the membrane of the pudendal nerve PN, creating the block and preventing further depolarization and action potential propagation. The field lines shown in Figs. 23A-23B are only representative of the electrical field between the contact electrodes 82c, 82d and the electrical field between the contact electrodes 82d, 82e. In reality, the electrical fields between the contact electrodes 82c, 82d and the contact electrodes 82d, 82e will have many more field lines. For example, although the field lines of the electrical fields are only shown in Fig. 23B on the top half of the contact electrodes 82c-82e for purposes of brevity, the field lines of the electrical fields will also exist on the bottom half of the contact electrodes 82c-82e. Furthermore, the respective polarizations of the contact electrodes 82c-82e are only illustrated in Fig. 23B during one half cycle of the neuromodulation energy provided to the electrodes 82c-82e. Thus, for one half cycle, the contact electrodes 82c-82e will have a particular polarization (in the illustrated case, the contact electrodes 82c and 82e have a positive polarization, and the contact electrode 82e has a negative polarization), and in the other half cycle, the polarization of the contact electrodes 82c- 82e will reverse to provide charge balance via biphasic delivery of the neuromodulation energy.

[0162] The approaches to minimize or eliminate cross-talk between the channels of a multi-channel neuromodulation system, especially one that requires multiple independent, concurrently activated channels, will now be described with respect to percutaneous, transcutaneous, and fully implantable neuromodulation systems. [0163] In the case of percutaneous neuromodulation systems, since the electrical power and signal generator circuits are external to the body, electrical isolation between channels can be achieved with separate independent external power sources and neuromodulation circuits for each channel of a multi-channel percutaneous neuromodulation system. This approach would be useful particularly when the percutaneous neuromodulation system is tasked to deliver nonsimilar neuromodulation concurrently to several independent channels.

[0164] In the case of transcutaneous neuromodulation systems, in contrast to the transcutaneous neuromodulation system 120 illustrated in Fig. 10, which has a passive receiver- neuromodulator 124 with a single power coil for the two channels (Channels CHx and CHy), a transcutaneous neuromodulation system 120a in accordance with one approach electrically isolates Channels CHx and CHy from each other by having two separate and independent power coils for passive receiver-neuromodulators 124a, 124b respectively for the two channels (Channels CHx and CHy), as illustrated in Fig. 24. Since the neuromodulation current circulates within its own closed circuit, there is minimal cross-talk between the two channels (Channels CHx and CHy) in this scenario.

[0165] In contrast to transcutaneous neuromodulation system 120 illustrated in Fig. 10, which also has an external power source 122 with a single drive coil for the two channels (Channels CHx and CHy), a transcutaneous neuromodulation system 120b in accordance with another approach electrically isolates Channels CHx and CHy from each other by not only having two separate and independent power coils for the passive receiver-neuromodulator 124 respectively for the two channels (Channels CHx and CHy), but also has two separate and independent drive coils for the external power source 122, as illustrated in Fig. 25. In this case, the two channels (Channels CHx and CHy) may have different neuromodulation parameters while being concurrently activated and minimizing cross-talk between the two channels (Channels CHx and CHy).

[0166] In contrast to the transcutaneous neuromodulation system 140 illustrated in Fig. 11, in which the ground between the two channels (Channels CHx and CHy) is shared, a transcutaneous neuromodulation system 140a in accordance with one approach electrically isolates Channels CHx and CHy from each other by having separate ground terminals 152a, 152b that float relative to each other, as illustrated in Fig. 26, thereby minimizing or eliminating cross-talk.

[0167] In the case of fully implantable neuromodulation systems, preventing or minimizing cross-talk is not straightforward, given several competing design constraints that include size, weight, power consumption, reliability, heat generation, manufacturability, cost, and neuromodulation delivery capacity. In contrast to fully implantable neuromodulation system 160 illustrated in Fig. 12, in which the ground between the two channels (Channels CHx and CHy) is shared, a fully implantable neuromodulation system 160a in accordance with one approach electrically isolates Channels CHx and CHy from each other by having separate ground terminals 168a, 168b that float relative to each other, as illustrated in Fig. 27. Thus, despite the presence of cross-talk paths, the two separate grounds confine each channel’s neuromodulation current to that channel’s electrical circuit, thereby preventing cross-talk between the two channels (Channels CHx and CHy).

[0168] To minimize or eliminate undesirable action potential generation generated by undesirable cross-talk, it is necessary to electrically isolate at least N-l channels of a neuromodulation system that concurrently activates an N number of channels that potentially have significant cross-talk between the channels. In one embodiment, the neuromodulation system has a total of N channels. In other embodiments, the neuromodulation system may have more than N channels, but only an N number of channels are concurrently and independently activated. In still other embodiments, the neuromodulation system may concurrently and independently activate more than an N number of channels, but only an N number of those concurrently and independently activated channels are susceptible to significant cross-talk.

[0169] While it is possible to minimize cross-talk by isolating all such N channels for percutaneous and transcutaneous neuromodulators, for fully implantable neuromodulation systems, it is more practical to isolate, at a minimum, N-l channels. This N-l approach has the benefits of reducing complexity, thus improving reliability and manufacturability, reducing power consumption through heat dissipation, and reducing IPG size and cost. Thus, in this case, the micturition management system 10, which has three independent channels (i.e., Bipolar Channel CHI and Tripolar Channels CH2-CH3), electrically isolates two of the three channels. As will be described in further detail below, the micturition management system 10 electrically isolates Tripolar Channels CH2-CH3.

[0170] There are several ways in which the channel isolation illustrated in Fig. 27 can be achieved by the micturition management system 10. In each of the approaches described below, in accordance with the general rule to electrically isolate at least N-l channels of a neuromodulation system that concurrently and independently activates an N number of channels that are susceptible to cross-talk, Tripolar Channels CH2-CH3 in the micturition management system 10 are electrically isolated, while Bipolar Channel CHI in the micturition management system 10 is not electrically isolated so all three channels have separate grounds.

[0171] For example, referring to Fig. 28, one multi-channel isolation technique that can be implemented in the micturition management system 10 will be described. The IPG 16 of the micturition management system 10 further comprises two electrical isolation barriers 86 located between the signal generators 42b-42c corresponding to Tripolar Channels CH2-CH3 and the respective lead electrode assemblies 26b-26c. These electrical isolation barriers 86 isolate Tripolar Channels CH2-CH3 from each other, as well as isolate Tripolar Channels CH2-CH3 from Bipolar Channel CHI.

[0172] In one embodiment, the two electrical isolation barriers 86 take the form of transformers 86a, 86b, as illustrated in Fig. 29. In the illustrated embodiment, the transformers 86a, 86b are ferrite-core transformers with operating frequencies in the kHz (audio) range (i.e., audio step-up transformers). Because the transformers 86a, 86b are naturally in the range of the desired high frequency signals generated for Tripolar Channels CH2-CH3, the electrical isolation barriers 86 are easy to implement in the IPG 16.

[0173] In contrast to Fig. 8, which illustrates cross-talk between non-isolated Bipolar Channel CHI and non-isolated Tripolar Channels CH2-CH3, the cross-talk between non-isolated Bipolar Channel CHI and isolated Tripolar Channels CH2-CH3 has been minimized. As a result, no action potentials will propagate from Tripolar Channels CH2-CH3, such that the external urethral sphincter EUS will not contract during the Void mode. Furthermore, the much lower signal amplitude signal of Bipolar Channel CHI continues to be transmitted to the bladder B without the risk of being overwhelmed by the much higher amplitude blocking signals of Tripolar Channels CH2-CH3. As such, the micturition management system 10 may initiate and sustain efficient voiding of the bladder B during the Void Mode.

[0174] The manner in which the transformers 86a, 86b electrically isolate Bipolar Channel CHI and Tripolar Channels CH2-CH3 from each other will now be described. Referring first to Fig. 30, Bipolar Channel CHI associated with the lead electrode assembly 26a and bipolar contact electrodes 82a-82b as shown as stimulating the left pudendal nerve PN, while Tripolar Channels CH2-CH3 respectively associated with the lead electrode assemblies 26b-26c and tripolar contact electrodes 82c- 82e are shown as blocking the left and right pudendal nerves PNs.

[0175] If Bipolar Channel CHI and Tripolar Channels CH2-CH3 all share the same ground, then they will not be isolated from each other, and thus, susceptible to generating crosstalk when they are concurrently activated.

[0176] For example, with reference to Fig. 31, the lead electrode assemblies 26a-26c are respectively represented by resistances R1-R3, and the signal generators 42a-42c are represented by power sources S1-S3 and are shown as sharing the same ground. During normal operation, electrical currents i 1 -i3 (denoted by the solid arrows) respectively flow through the three circuits corresponding to Bipolar Channel CHI and Tripolar Channels CH2-CH3. However, since all of the lead electrode assemblies 26a-26c are inside of the body, many leakage paths will be created in the circuits. Two such leakage paths represented by a resistance Rleakl2 between the lead electrode assembly 26a of Bipolar Channel CHI and the lead electrode assembly 26b of Tripolar Channel CH2 and a resistance Rleak23 between the lead electrode assemblies 26b-26c of Tripolar Channel CH2-CH3 will be created. Another leakage path (not shown) will be created between the lead electrode assembly 26a of Bipolar Channel CHI and the lead electrode assembly 26c of Tripolar Channel CH3.

[0177] Since the signal generator SI of Bipolar Channel CHI and the signal generator S2 of Tripolar Channel CH2 share the same ground, electrical leakage current il-2 (denoted by dashed arrow) will flow through a leakage path Rleakl2 between Bipolar Channel CHI and Tripolar Channel CH2. Similarly, since the signal generator SI of Bipolar Channel CHI and the signal generator S3 of Tripolar Channel CH3 share the same ground, electrical leakage current will flow through a leakage path (not shown) between Bipolar Channel CHI and Tripolar Channel CH3. In a similar fashion, since the signal generators S2-S3 of Tripolar Channel CH2- CH3 share the same ground, electrical leakage current i2-3 (denoted by dashed arrow) will flow through a leakage path Rleak23.

[0178] However, because the micturition management system 10 includes two electrical isolation barriers 86 that are located between the signal generators 42b-42c corresponding to Tripolar Channels CH2-CH3 and the respective lead electrode assemblies 26b-26c, Tripolar Channels CH2-CH3 will float and will no longer share the same ground with Bipolar Channel CHI. As such, Bipolar Channel CHI and Tripolar Channels CH2-CH3 will all be electrically isolated from each other.

[0179] In particular, and with reference to Fig. 32, a representative circuit that includes a signal generator S, a load resistance Rload, and a transformer T coupled between the signal generator S and the load resistance Rload will be described. The transformer has a primary side PS having a coil inductance Lp and a secondary side SS having a coil inductance Ls. Electrical current Ip in the primary side PS passes only through the inductance Lp, while electrical current Is in the secondary side SS passes only through the inductance Ls. In other words, there is no path for the current to “leak” from the primary side PS to the secondary side SS.

[0180] Thus, as illustrated in Fig. 33, when transformers T2-T3 are coupled between the signal generators 42b-42c (shown as S2-S3 in Fig. 33) and the lead electrode assemblies 26b-26c (shown as R2-R3 in Fig. 33), Tripolar Channels CH2-CH3 will be floating and will not be connected to the ground of Bipolar Channel CHI. Current II will flow through the circuit corresponding to Bipolar Channel CHI, current I2p and I2s will respectively flow through the primary side PS and secondary side SS of the transformer T2 corresponding to Tripolar Channel CH2, and current I3p and 13 s will respectively flow through the primary side PS and secondary side SS of the transformer T3 corresponding to Tripolar Channel CH3. However, there will be no current flowing through the leakage path Rleakl2 between Bipolar Channel CHI and Tripolar Channel CH2, no current flowing through the leakage path Rleakl3 (not shown) between Bipolar Channel CHI and Tripolar Channel CH3, and no current flowing through the leakage path Rleak23 between Tripolar Channels CH2-CH3. [0181] In an alternative technique, rather than have the two electrical isolation barriers 86 located between the signal generators 42b-42c corresponding to Tripolar Channels CH2-CH3 and the respective lead electrode assemblies 26b-26c, as illustrated in Fig. 28, the two electrical isolation barriers 86 are located between the power and control circuitry 54 and the signal generators 42b-42c, as illustrated in Fig. 34. In this case, both power and signal have to be isolated by isolation barrier 86.

[0182] In one embodiment, the two electrical isolation barriers 86 respectively comprise high frequency transformers 86c, 86d (DC-to-DC converters) and optical signal isolators 88a, 88b, as illustrated in Fig. 35. The high frequency transformers 86c, 86d transfer power from the power and control circuitry 54 to the signal generators 42b-42c corresponding to Tripolar Channels CH2-CH3 and the respective lead electrode assemblies 26b-26c. In this case, DC power is converted to high frequency AC power that passes through the coils of the high frequency transformers 86c, 86 for isolation, which isolated high frequency AC power is then converted back to DC power. The optical signal isolators 88a, 88b respectively relay control signals from the power and control circuitry 54 to the signal generators 42b-42c corresponding to Tripolar Channels CH2-CH3 and the respective lead electrode assemblies 26b-26c. Thus, the high frequency transformers 86c, 86d and optical signal isolators 88a, 88b allow for complete electrical isolation of Tripolar Channels CH2-CH3 with respect to each other and with respect to Bipolar Channel CHI.

[0183] In this case, the micturition management system 10 would have no iron-based magnetic coupling in the high frequency transformers 86c, 86d. Since the operating frequencies of the high frequency transformers 86c, 86d are in the MHz range, as compared to the kHz operating frequencies of the ferrite-core transformers 86c, 86d of the micturition management system 10 of Fig. 28, the amount of ferromagnetic material in each of the transformers 86c, 86d is reduced. This might potentially allow the patient to be imaged with Magnetic Resonance Imaging (MRI). Furthermore, the high frequency transformers 86c, 86d have a relatively small footprint, thereby reducing the size and power requirements of the IPG 16.

[0184] In another embodiment, the two electrical isolation barriers 86 respectively comprise piezo-electrical transformers 86e, 86f and previously described optical signal isolators 88a, 88b, as illustrated in Fig. 36. The piezo-electrical transformers 86e, 86f transfer power (by converting electricity to mechanical piezo-electric forces that are then converted back into electricity to provide the electrical isolation) from the power and control circuitry 54 to the signal generators 42b-42c corresponding to Tripolar Channels CH2-CH3 and the respective lead electrode assemblies 26b-26c, while the optical signal isolators 88a, 88b respectively relay control signals from the power and control circuitry 54 to the signal generators 42b-42c corresponding to Tripolar Channels CH2-CH3 and the respective lead electrode assemblies 26b- 26c. Thus, the piezo-electrical transformers 86e, 86f and optical signal isolators 88a, 88b allow for complete electrical isolation of Tripolar Channels CH2-CH3 with respect to each other and with respect to Bipolar Channel CHI.

[0185] In still another embodiment, only one electrical isolation barrier 86 is located between the power and control circuitry 54 and the signal generators 42b-42c, as illustrated in Fig. 37. In this case, the electrical isolation barrier 86 comprises a ferrite-core transformer 86g with an operating frequency in the kHz range, although the electrical isolation barrier 86 may alternatively comprise a high frequency transformer, such as one of the high frequency transformers 86c, 86d illustrated in Fig. 35 or a piezo-electrical transformer, such as one of the piezo-electrical transformers 86e, 86f illustrated in Fig. 36. In these latter cases, a signal isolation method is also provided. In this embodiment, Tripolar Channels CH2-CH3 will be activated with the same neuromodulation parameters (same amplitude, frequency, phase, and waveform shape), but different from the neuromodulation parameters with which Bipolar Channel CHI will be activated. Thus, Tripolar Channels CH2-CH3 need not be independent relative to each other, and can be driven together by a single isolation means. This configuration reduces the number N of independent channels to two: Bipolar Channel CHI and Tripolar Channel CH2/CH3, still requiring N-l = 1 isolated channel to avoid cross-talk, thereby preventing stimulation and contraction of the external urethral sphincter EUS that may otherwise prevent urination when the micturition management system 10 is operating in the Void Mode. It should be appreciated that in the context of neuromodulation treatment for bladder dysfunction, it is desirable for Tripolar Channels CH2-CH3 to be independent and electrically isolated from each other, since the Tripolar Channels CH2-CH3 will, in practice, be activated with different neuromodulation parameters. As such, the use of only one electrical isolation barrier 86 between the power and control circuitry 54 and the signal generators 42b-42c may not be optimal. However, in the context of other neuromodulation applications, it may be practically possible for two independent channels to not be electrically isolated from each other, while electrically isolating a third independent channel from the two non-isolated independent channels.

[0186] In all of the embodiments illustrated in Figs. 28-37, each of electrically isolated Tripolar Channels CH2-CH3 cannot only deliver the desired electrical neuromodulation (amplitude, frequency, phase in relation to Bipolar Channel CHI), but also the precise amplitude level of the neuromodulation energy delivered to the lead electrodes assembly 26b-26c can be determined as a source of feedback to enable closed-loop control of the delivered neuromodulation energy through Tripolar Channels CH2-CH3.

[0187] Although the amplitude level of the neuromodulation energy delivered through non-isolated Bipolar Channel CHI to the lead electrode assembly 26a is straightforward by using means of direct measurement, directly measuring the amplitude level of the neuromodulation energy delivered through isolated Tripolar Channels CH2-CH3 at the lead electrode assemblies 26b-26c would interfere with the desired isolation of Tripolar Channels CH2-CH3. Thus, it is important to measure the amplitude level of the delivered neuromodulation energy on the nonisolated side of each of Tripolar Channels CH2-CH3. This implies the use of some method of estimating the amplitude level of the delivered neuromodulation energy at the lead electrode assemblies 26b-26c. Based on this estimation, the amplitude level of the delivered neuromodulation energy in Tripolar Channels CH2-CH3 can be adjusted by the processing circuitry 56 (shown in Fig. 3), so that precise amplitude level of desired neuromodulation can be achieved. In the illustrated embodiment, the output current for Tripolar Channels CH2-CH3 covers a range of 0.2 mA to 14 mA and is established through calculation of load impedance and setting a channel supply voltage level to get desired current at lead electrode assemblies 26b-26c. The processing circuitry 56 may indirectly control the amplitude level of the delivered neuromodulation energy in Tripolar Channels CH2-CH3 under control of the external patient controller 18 or clinician programmer 20, or alternatively may directly control the amplitude level of the delivered neuromodulation energy in Tripolar Channels CH2-CH3 without intervention by the external patient controller 18 or clinician programmer 20. Calculation of load impedance and determination of set point to achieve desired output can be performed externally in the external patient controller 18 or clinician programmer 20 and delivered to the IPG 16 via telemetry, or may be performed in the IPG 16 itself using firmware.

[0188] Setting the amplitude level of the delivered neuromodulation energy begins when a user sets the amplitude through the external patient controller 18 or clinician programmer 20), which then transmits instructions to the IPG 16 through radio telemetry. The IPG 16 then uses the incoming instructions to provide a certain current (for Channel CHI) or a certain voltage (for Channels CH2-CH3) for delivery of the neuromodulation energy. In one embodiment, the clinician programmer 20 is used to transmit instructions (containing various combinations of neuromodulation parameters) to the IPG 16 via the external patient controller 18 during a fitting session, and define the neuromodulation programs (each of which contains a set of neuromodulation parameters) based on feedback from the fitting session. Such neuromodulation programs can then be stored in the external patient controller 18, which can be selected activated and modified in a limited manner by the patient, to effect the desired therapy for DO/DSD. Due to clinical convention dictating nerve modulation using neuromodulation energy in the milliamperes and that the signal generators 42b-42c of the IPG 16 comprise constant voltage sources, estimation of the nerve impedance is required to determine the amplitude level of the delivered neuromodulation energy for Tripolar Channels CH2-CH3. It is possible to use a set of equations built on interpolations within lookup tables. For example, the nerve impedance can be first calculated and used along with the amplitude and frequency set by the user in the IPG 16 to determine the necessary voltage supply. However, while this technique does function well during most settings, certain settings may result in inaccurate determination of the voltage supply. Also, lookup tables must be created from a large amount of units to ensure that determination of voltage supply values are accurate.

[0189] Instead, the micturition management system 10 employs an adaptive neuromodulation technique that uses a mathematical model that takes into account the load impedance (including the implanted neuromodulation lead assemblies 12, the lead electrode assemblies 26, and any objects attached to the lead electrode assemblies 26, set frequency, set amplitude level of the delivered neuromodulation energy (in this case, the electrical current level), and measured current in the IPG 16. The mathematical model is adaptive in the sense that it can handle minor variations between units and still achieve accurate results. This adaptive neuromodulation technique calculates the load impedance, then determines the correct channel supply voltage needed for the set amplitude level of the delivered neuromodulation energy. As updates for the measured current in the IPG 16 are acquired, the load impedance and the correct channel supply voltage are recalculated. This process repeats until the delivered current is either within a percentage of the set amplitude level of the delivered neuromodulation energy or a defined maximum number of iterations have occurred. In the illustrated embodiment, the adaptive neuromodulation technique is performed during an initial period (e.g., the first 1-5 seconds) of the Void Mode. Furthermore, in the illustrated embodiment, the adaptive neuromodulation technique is performed by the clinician programmer 20 during the initial fitting session, as well as any follow-up sessions that take into account changes in impedances at the lead electrode assemblies 26, and in other parts of the neuromodulation parameter delivery circuitry.

[0190] The mathematical model is first generated by characterizing the internal electronic components in the IPG 16 that are indicative of the load impedance, based on manufacturer specification and/or bench testing. In the illustrated embodiment, the electronic components to be characterized include the transformer 86 (86a or 86b), the resistance of the switch 48 of the signal output circuitry 42 (signal generator 42b or signal generator 42c), and the voltage drop of each diode 90 at the output of the low range voltage source 46a and high range voltage source 46b, as illustrated in Fig. 38. The monitoring circuity 50 includes a current sensing circuit for sensing the electrical current at the input of the switch 48.

[0191] In the illustrated embodiment, the transformer 86 is an audio step-up transformer (e.g., PICO 78115) with a 1.0:1.41 ratio, which was selected for its capability to provide increased neuromodulation at greater loads. The mathematical model for the transformer 86 can be deduced through bench testing and is represented by the equivalent circuit illustrated in Fig. 39, and the equations [l]-[4].

[1] r_in=25Q;

[2] L_p=73.608*f ^A (- 1.045) H;

[3] R_p=10 ^A (-9)*f ^A 2+0.0019*f+57.367Q; and [0192] [4] C_p=0.0182*f ^A (-1.578) F, where rin is the input resistance, Lp is the primary leakage inductance with parallel equivalent resistance Rp, primary capacitance Cp, f is the set frequency, H is Henries, and F is Farads.

[0193] The input resistance rin may be provided by the manufacturer’s component specifications. The primary leakage inductance Lp, resistance Rp, and primary capacitance Cp can be measured with an instrument (e.g., Agilent 4263B LCR meter) with a sufficient voltage (e.g., 1.0 V) at a sufficient number of frequency intervals (e.g., 100, 120, 1000, 10,000, and 100,000 Hz). The primary capacitance Cp can be measured across the primary windings of the transformer 86 with the secondary windings of the transformer 86 open.

[0194] All measurements can be plotted in a suitable program (e.g., Microsoft Excel) and interpolated to create equations [l]-[4]. For example, Table 1 below presents the observed measurements of the primary leakage inductance Lp over the frequency range, which can be plotted and fitted with a power function, as illustrated in Fig. 40. Table 2 below presents the observed measurements of the parallel equivalent resistance Rp over the frequency range, which can be plotted and fitted with a power function, as illustrated in Fig. 41. Table 3 below presents the observed measurements of the primary capacitance Cp over the frequency range, which can be plotted and fitted with a power function, as illustrated in Fig. 42.

Table 1

100 0.519

120 0.5

1000 0.0983

10,000 0.0022 Table 2

Table 3

[0195] The resistance of the switch 48 of the signal output circuitry 42 can also be modeled using the manufacturer’s specifications. In the illustrated embodiment, the switch 48 is a DG9426E Quad SPST Switch. The resistance of the switch 48 changes with the channel supply voltage, which supplied from the higher of a regulated voltage (e.g., 3V) and a DC/DC converter (e.g., up to 12V) in order to provide a high blocking current, thereby leading to a change in the resistance with neuromodulation intensity, leading to the resistance to change with neuromodulation intensity. The resistance Ron of the switch 48 can be measured with an instrument (e.g., Agilent 4263B LCR meter) at a sufficient number of voltage intervals (e.g., 3, 5, 10, 12 V). Table 4 below presents the observed measurements of the resistance Ron of the switch 48 over a voltage range, which can be plotted and curve fitted of manufacturer data, as illustrated in Fig. 43. Table 4

[0196] The measurements for the resistance Ron of the switch 48 can be plotted in a suitable program (e.g., Microsoft Excel) and interpolated to create equations [5] below.

[5] R=15.283V ^A (-0.917) , where R is the resistance of switch 48, V is the channel supply voltage, and is ohms.

[0197] Lastly, the voltage drop Vdiode of each diode 80 can be modeled for a given internal measured current at 25°C using a manufacturer’s I-V graph illustrated in Fig. 44, and used to create equation [6] below. In the illustrated embodiment, each diode 80 is a CDBQR0130L Schottky diode. [6] Vdiode ⁼ 0.1709 * I f ( nA)° ¹⁵³⁸ V, where Vdiode is the voltage across the diode 80, If is the electrical current through the diode 80, mA is milliamperes, and V is the forward voltage.

[0198] The current channel supply voltage from the active one of the low range voltage source 46a or high range voltage source 46b, internal current measurement from the current sensing circuit of the monitoring circuitry 50, voltage drop over the diode 80 coupled to the active one of the low range voltage source 46a or high range voltage source 46b, and the model of the transformer 86 can be used to calculate the load impedance on the secondary side of the transformer 86.

[0199] The adaptive neuromodulation technique adjusts the neuromodulation level of the IPG 16 for the calculated load and frequency of Tripolar Channels CH2-CH3. This is accomplished by setting the channel supply voltage for each Tripolar Channel CH2-CH3 to a value that will correspond with the required voltage on the secondary side of the transformer 86 to achieve the desired neuromodulation intensity. For example, if a user sets the IPG 16 via the external patient controller 18 to output 5 mA at 6 kHz with the implanted lead assembly 12 presenting a IkQ load, the adaptive neuromodulation technique adjusts the power supply (the low range voltage source 46a or the high range voltage source 46b) of each Tripolar Channel CH2-CH3, so that the voltage on the secondary side of the respective transformer 86 (86a or 86b) is 5.0 V. This is accomplished using the modeled equations [l]-[6] with the internal measured current of the IPG 16 and the set parameters (electrical current level and frequency). Once the correct channel supply voltage for the low range voltage source 46a or the high range voltage source 46b is calculated, it is converted into a digital programmable set point for an adjustable power supply if operating in the low current range (low range voltage source 46a is active) or a digital potentiometer value if operating in the high current range (high range voltage source 46b is active) and transmitted from the external patient controller 18 to the IPG 16 via radio telemetry.

[0200] In one embodiment, the monitoring circuitry 50 is configured for sensing an electrical parameter (and in particular, an electrical current) at the non-isolated side of each electrical isolators 86 of Tripolar Channels CH2-CH3. The processing circuitry in the external patient controller 18 (or the processing circuitry 56 of the IPG 16) is configured for estimating an intensity level of the delivered neuromodulation energy (and in particular, the amperage) at the isolated side of each electrical isolator 86 of Tripolar Channels CH2-CH3 based on the sensed electrical current at the non-isolated side of each electrical isolators 86 of Tripolar Channels CH2-CH3. In the illustrated embodiment, the processing circuitry in the external patient controller 18 accomplishes this by inputting a frequency and voltage into the mathematical model characterizing each of Tripolar Channels CH2-CH3 and the electrical isolators 86 (in this case, equations [l]-[6]) to estimate an impedance load at the isolated side of each electrical isolator 86 of Tripolar Channels CH2-CH3, and estimating the amperage of the delivered neuromodulation energy at the isolated side of each electrical isolator 86 of Tripolar Channels CH2-CH3 based on the estimated impedance load and channel supply voltage of the low range voltage source 46a or high range voltage source 46b.

[0201] Referring now to Fig. 45, one method 200 of operating the micturition management system 10 to treat a urinary dysfunction in a patient that produces symptoms of DO and DSD in the patient will be described.

[0202] First, a fitting session is conducted on the patient to define one or more neuromodulation programs and store these neuromodulation programs in the external patient controller 18 (step 204). After the fitting session, the IPG 16 may be operated in a stand-alone mode. In particular, the patient may use the external patient controller 18 to select a neuromodulation program, and send instructions corresponding to the selected neuromodulation program from the external patient controller 18 to the IPG 16 (step 206).

[0203] If the micturition mode of the micturition management system 10 is in the Fill Mode (step 208), neuromodulation energy is delivered from the IPG 16 through Bipolar Channel CHI to the pudendal nerve PN in accordance with a first set of neuromodulation parameters (and in particular, one having a frequency less than 15 Hz), thereby relaxing and promoting greater filling of the bladder B (step 210). In the illustrated embodiment, the micturition management system 10 automatically enters the Fill Mode after the Void Mode is completed.

[0204] If the micturition mode of the micturition management system 10 is in the Void Mode (step 208), neuromodulation energy is concurrently delivered from the IPG 16 through Bipolar Channel CHI and electrically isolated Tripolar Channels CH2-CH3 to the pudendal nerve PN in accordance with a second set of neuromodulation parameters for Bipolar Channel CHI (e.g., one having a frequency in the range of 20 Hz to 30 Hz) and a third set of neuromodulation parameters for Tripolar Channels CH2-CH3 (e.g., one having a frequency in the range of 2-20 kHz), thereby contracting the bladder B and blocking the external urinary bladder EUS from contracting, and promoting the voiding of the bladder B (step 212).

[0205] Referring to Fig. 46, one method 250 of adaptively adjusting the amperage level of the neuromodulation energy delivered through Tripolar Channels CH2-CH3 to match the intended amperage level of the delivered neuromodulation energy set by the clinician will be described. As will be described in further detail below, the method 250 is a process that iteratively adjusts the amperage level of the neuromodulation energy delivered through Tripolar Channels CH2-CH3 until it matches the intended amperage level of the delivered neuromodulation energy set by the clinician within a certain tolerance level. While the method 250 is described below as being hosted by a clinician programmer 20, it should be appreciated that, in alternative embodiments, the method 250 may be hosted in other devices, including the patient controller 18 or IPG 16.

[0206] First, the clinician programmer 20 receives a request to turn on the output of Tripolar Channels CH2-CH3 at a set amperage level and frequency as needed for voiding (step 252). The clinician programmer 20 then determines whether a load impedance has been previously estimated (step 254). If a load impedance has not been previously estimated, the clinician programmer 20 uses a default load impedance value (e.g., 1000 ohms) for the subsequent load impedance calculation (step 256). If a load impedance has been previously estimated, the clinician programmer 20 uses the previously estimated load impedance value for the subsequent load impedance calculation (step 258). The clinician programmer 20 then computes a channel supply voltage value needed to deliver the specified current using the mathematical model of equations [l]-[6] based on the load impedance and set amperage level and frequency of the delivered neuromodulation energy for Tripolar Channels CH2-CH3, and sets the low range voltage source 46a or high range voltage source 46b (by communicating instructions to the IPG 16) in accordance with the computed channel supply voltage value (step 260). [0207] Next, the IPG 16 directly measures the inner electrical current in the IPG 16 at the non-isolated sides of the electrical isolators 86 (step 262) (which measurement can be transmitted from the IPG 16 to the clinician programmer 20), and the clinician programmer 20 updates the estimated load impedance at the electrode assemblies 26b-26c of Tripolar Channels CH2-CH3 using the mathematical model of equations [l]-[6] based on the measured inner electrical current, channel supply voltage level (i.e., channel supply voltage of the low range voltage source 46a or high range voltage source 46b), and set frequency (step 264). The clinician programmer 20 then estimates the amperage level of the neuromodulation energy delivered through Tripolar Channels CH2-CH3 based on the estimated load impedance and channel supply voltage of the low range voltage source 46a or high range voltage source 46b, and set frequency (step 266).

[0208] The external patient controller 18 then determines if the estimated amperage level of the neuromodulation energy delivered through Tripolar Channels CH2-CH3 is within a certain percentage of the set amperage level for the delivered neuromodulation energy for Tripolar Channels CH2-CH3 (step 268). If the estimated amperage level of the neuromodulation energy delivered through Tripolar Channels CH2-CH3 is within a certain percentage of the set amperage level for the delivered neuromodulation energy for Tripolar Channels CH2-CH3 (e.g., within 2.5 percent), the iterations are stopped (step 270). If the estimated amperage level of the neuromodulation energy delivered through Tripolar Channels CH2-CH3 is not within a certain percentage of the set amperage level for the delivered neuromodulation energy for Tripolar Channels CH2-CH3, the external patient controller 18 determines if the number of iterations has reached the maximum number (step 272).

[0209] If the maximum number of iterations has been reached, the iterations are stopped (step 270). If the maximum number of iterations has not been reached, the external patient controller 18 increments an iteration counter by one (step 274) and returns to step 260 where the external patient controller 18 recomputes an output voltage value based on the re-estimated load impedance and set amperage level and frequency of the delivered neuromodulation energy for Tripolar Channels CH2-CH3, and resets the low range voltage source 46a or high range voltage source 46b in accordance with the recomputed output voltage value. [0210] Although the techniques for independently and concurrently activating channels have been described herein as treating urinary dysfunction, and in particular, DO and DSD, the clinical relevance of such techniques can be expanded. Other applications related to pudendal nerve modulation are sexual dysfunction restoration and enhancement, and bowel function regulation. Besides these applications, there are much broader clinical scenarios in which the independent and concurrent activation of channels can be applied. Furthermore, techniques for independently and concurrently activating channels have been described herein for the treatment of humans, and it should be appreciated that such treatments can be used to treat any one of a variety of disorders of animals.

[0211] Although particular embodiments of the present inventions have been shown and described, it will be understood that it is not intended to limit the present inventions to the preferred embodiments, and it will be obvious to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the present inventions. Thus, the present inventions are intended to cover alternatives, modifications, and equivalents, which may be included within the spirit and scope of the present inventions as defined by the claims.