The effects of neuromodulation in a novel obese-prone rat model of detrusor underactivity.

Obesity is a global epidemic associated with an increased risk for lower urinary tract dysfunction. Inefficient voiding and urinary retention may arise in late-stage obesity when the expulsive force of the detrusor smooth muscle cannot overcome outlet resistance. Detrusor underactivity (DUA) and impaired contractility may contribute to the pathogenesis of nonobstructive urinary retention. We used cystometry and electrical stimulation of peripheral nerves (pudendal and pelvic nerves) to characterize and improve bladder function in urethane-anesthetized obese-prone (OP) and obese-resistant (OR) rats following diet-induced obesity (DIO). OP rats exhibited urinary retention and impaired detrusor contractility following DIO, reflected as increased volume threshold, decreased peak micturition pressure, and decreased voiding efficiency (VE) compared with OR rats. Electrical stimulation of the sensory branch of the pudendal nerve did not increase VE, whereas patterned bursting stimulation of the motor branch of the pudendal nerve increased VE twofold in OP rats. OP rats required increased amplitude of electrical stimulation of the pelvic nerve to elicit bladder contractions, and maximum evoked bladder contraction amplitudes were decreased relative to OR rats. Collectively, these studies characterize a novel animal model of DUA that can be used to determine pathophysiology and suggest that neuromodulation is a potential management option for DUA.

Stimulation of the pelvic nerve increases bladder capacity in the prostaglandin E2 rat model of overactive bladder.

Overactive bladder (OAB) syndrome is a highly prevalent condition that may lead to medical complications and decreased quality of life. Emerging therapies focusing on selective electrical stimulation of peripheral nerves associated with lower urinary tract function may provide improved efficacy and reduced side effects compared with sacral neuromodulation for the treatment of OAB symptoms. Prior studies investigating the effects of pelvic nerve (PelN) stimulation on lower urinary tract function were focused on promoting bladder contractions, and it is unclear whether selective stimulation of the PelN would be beneficial for the treatment of OAB. Therefore our motivation was to test the hypothesis that PelN stimulation would increase bladder capacity in the prostaglandin E2 (PGE2) rat model of OAB. Cystometry experiments were conducted in 17 urethane-anesthetized female Sprague-Dawley rats. The effects of intravesical PGE2 vs. vehicle and PelN stimulation after intravesical PGE2 on cystometric parameters were quantified. Intravesical infusion of PGE2 resulted in decreased bladder capacity and increased voiding efficiency without a change in bladder contraction area under the curve, maximum contraction pressure, or contraction duration. Bladder capacity was also significantly decreased compared with vehicle (1% ethanol in saline) confirming that the change in bladder capacity was mediated by PGE2 PelN stimulation reversed the PGE2-induced change in bladder capacity and increased the external urethral sphincter electromyogram activity at a specific stimulation condition (amplitude of 1.0 times threshold at 10 Hz). These results confirm that the urodynamic changes reported in conscious rats are also observed under urethane anesthesia and that PelN stimulation is a novel and promising approach for the treatment of the symptoms of OAB.

Inferior hypogastric plexus blockade versus acupuncture for the management of idiopathic chronic pelvic pain: A randomized clinical trial.

BACKGROUND: To compare the clinical efficacies of inferior hypogastric plexus blockade and acupuncture in the management of idiopathic chronic pelvic pain (CPP). METHODS: The study included 117 patients with CPP. Group 1 included 62 patients who underwent inferior hypogastric plexus blockade and group 2 included 55 patients who underwent acupuncture. Pain level was assessed using a visual analogue scale (VAS) immediately and at 2, 6, and 12 weeks after treatment. RESULTS: The preprocedure VAS score was 7.6 ± 0.15 in group 1 and 7.7 ± 0.24 in group 2 (p > 0.05). Pelvic pain decreased significantly in both groups after treatment, with pretreatment and posttreatment scores of 7.6 ± 0.15 and 2.2 ± 0.88, respectively, in group 1 (p < 0.0001) and 7.7 ± 0.24 and 4.7 ± 0.11, respectively, in group 2 (p < 0.0001). However, the decrease in pain scores throughout the clinical follow-up was significantly more in group 1 than in group 2 (p< 0.0001). Complete disappearance of symptoms was achieved in 72.6% of patients in group 1 compared to 54.5% of patients in group 2 (p = 0.3737). Patients who did not benefit from the treatment were significantly more in group 2 than in group 1 (25.5% vs. 6.5%, p = 0.0294). No complications were reported in both groups. CONCLUSION: The study results showed that inferior hypogastric blockade had a 72.6% success rate and showed a significantly higher effect on reducing pain intensity in a short period of time in the management of CPP, compared to acupuncture.

Recruitment of intracavernously injected adipose-derived stem cells to the major pelvic ganglion improves erectile function in a rat model of cavernous nerve injury.

BACKGROUND: Intracavernous (IC) injection of stem cells has been shown to ameliorate cavernous-nerve (CN) injury-induced erectile dysfunction (ED). However, the mechanisms of action of adipose-derived stem cells (ADSC) remain unclear. OBJECTIVES: To investigate the mechanism of action and fate of IC injected ADSC in a rat model of CN crush injury. DESIGN, SETTING, AND PARTICIPANTS: Sprague-Dawley rats (n=110) were randomly divided into five groups. Thirty-five rats underwent sham surgery and IC injection of ADSC (n=25) or vehicle (n=10). Another 75 rats underwent bilateral CN crush injury and were treated with vehicle or ADSC injected either IC or in the dorsal penile perineural space. At 1, 3, 7 (n=5), and 28 d (n=10) postsurgery, penile tissues and major pelvic ganglia (MPG) were harvested for histology. ADSC were labeled with 5-ethynyl-2-deoxyuridine (EdU) before treatment. Rats in the 28-d groups were examined for erectile function prior to tissue harvest. MEASUREMENTS: IC pressure recording on CN electrostimulation, immunohistochemistry of the penis and the MPG, and number of EdU-positive (EdU+) cells in the injection site and the MPG. RESULTS AND LIMITATIONS: IC, but not perineural, injection of ADSC resulted in significantly improved erectile function. Significantly more EdU+ ADSC appeared in the MPG of animals with CN injury and IC injection of ADSC compared with those injected perineurally and those in the sham group. One day after crush injury, stromal cell-derived factor-1 (SDF-1) was upregulated in the MPG, providing an incentive for ADSC recruitment toward the MPG. Neuroregeneration was observed in the group that underwent IC injection of ADSC, and IC ADSC treatment had beneficial effects on the smooth muscle/collagen ratio in the corpus cavernosum. CONCLUSIONS: CN injury upregulates SDF-1 expression in the MPG and thereby attracts intracavernously injected ADSC. At the MPG, ADSC exert neuroregenerative effects on the cell bodies of injured nerves, resulting in enhanced erectile response.

Neuromodulation of the superior hypogastric plexus: a new option to treat bladder atonia secondary to radical pelvic surgery?

BACKGROUND: The aim of this study is to report on the impact of neuromodulation to the superior hypogastric plexus in patients with bladder atonia secondary to pelvic surgery. METHODS: In 4 consecutive patients with bladder atonia secondary to pelvic surgery, we performed a laparoscopic implantation of a neurostimulator--LION procedure--to the entire superior hypogastric plexus. RESULTS: Of the 4 reported patients, 3 are able to partially void or empty their bladder. CONCLUSIONS: If the presented results could be obtained in further patients and maintained in long-term follow-up, the LION procedure to the superior hypogastric plexus could change the management of bladder function in patients with bladder atonia.

Spinal cord stimulation is an effective treatment for the chronic intractable visceral pelvic pain.

OBJECTIVE: Recent studies have demonstrated significant involvement of dorsal column pathways in transmission of visceral pelvic pain. Spinal cord stimulation (SCS) suppresses visceral response to colon distension in an animal model and therefore may be an effective therapy for chronic pelvic pain of visceral origin. We are reporting on the value of neurostimulation for chronic visceral pelvic pain in six female patients with the diagnosis of long-standing pelvic pain (history of endometriosis, multiple surgical explorations, and dyspareunia). DESIGN AND SETTINGS: Case-series report. All patients received repeated hypogastric blocks (in an average of 5.3 blocks) with a significant pain relief for a period ranging from 1 to 6 weeks. Three received neurolytic hypogastric block with the pain relief of 3, 8, and 12 months, respectively. Following psychological evaluation and clearance by our Multidisciplinary Committee on Implantable Devices, they all underwent SCS trial for 7-14 days. All patients received SCS systems with dual leads (Compact or Quad leads, Medtronic Inc., Minneapolis, MN, USA). RESULTS: The average follow-up was 30.6 months. Median visual analog scale pain score decreased from 8 to 3. All patients had more than 50% of the pain relief. Pain Disability Index changed from an average of 57.7 +/- 12 to 19.5 +/- 7. Opiate use decreased from an average 22.5 mg to 6.6 mg of morphine sulfate milligram equivalents per day. CONCLUSION: It appears that SCS may have a significant therapeutic potential for treatment of visceral pelvic pain.

A spinal cord injured animal model of lower urinary tract function: observations using direct bladder and pelvic plexus stimulation with model microstimulators.

BACKGROUND: Microstimulators are new devices that should be considered for management of lower urinary tract problems following spinal cord injury (SCI) such as urinary retention. These devices are small (less than 25 mm by 5 mm) with the electrodes located on the ends of the stimulator. However, it is not known whether the small electrodes on these devices would be effective in stimulating the plexus of nerves that innervate the bladder. The aim of the present study was to provide preliminary observations with model microstimulators (M-Micro) for inducing bladder contractions in an SCI animal model. Bladder wall and pelvic plexus stimulation sites were compared. Additional investigations evaluated parameters such as stimulation polarity, frequency, and period as well as bladder filling volume. METHODS: In an initial survival surgery, bilateral M-Micros were implanted on the bladder wall and the pelvic plexus along the urethra in 3 female cats. A second survival surgery was conducted 3 to 5 weeks later to produce a T1 0 SCI. Studies are reported following the second survival surgery. These studies included the effects of stimulation and bladder filling. RESULTS: The postmortem location of the implanted pelvic plexus M-Micro was previously described as near the bladder neck. Therefore, the pelvic plexus location is described in this report as "pelvic plexus (bladder neck)" stimulation. The observations showed effective stimulation with pelvic plexus (bladder neck) stimulation and voiding in some cases. Stimulation was limited by side effects of increased abdominal pressure and leg movement. Other factors also affected the response to stimulation, including the initial bladder volume and stimulating parameters. Fluoroscopy showed that when stimulation did not induce voiding the striated urethral sphincter was closed. CONCLUSIONS: This case series of 3 SCI animals showed that the small electrodes on the M-Micro could be used to stimulate the bladder with contractions and voiding in some cases. The pelvic plexus (bladder neck) location for the M-Micro may be a better location than higher on the bladder wall. Limiting side effects of stimulation included leg movement and increased abdominal pressure. Additional important factors included the stimulation parameters, initial bladder volume, and the function of the skeletal urethral sphincter.

Chronic instrumentation with model microstimulators in an animal model of the lower urinary tract.

BACKGROUND: Microstimulators are a new type of neuroprosthetic device that should be considered for applications such as micturition control after spinal cord injury (SCI). These devices are small (less than 25 mm by 5 mm) and the electrodes are located on the ends of the stimulator. The aim of the current study was to develop methods for chronic implantation of model microstimulators (M-Micro) on the bladder wall and pelvic plexus of female cats. A postmortem evaluation of the effects of 3 months of implantation is reported. METHODS: Techniques to produce the M-Micro are described. Four of these devices were implanted in 4 female cats and maintained after the initial instrumentation surgery and a second survival surgery for SCI (at T10). Using a single suture tied around the M-Micro, these devices were secured to the bladder wall or the fat pads adjacent to the pelvic plexus. Additional instrumentation was implanted, including 2 catheters in the bladder, 1 abdominal balloon, and electromyography electrodes in the urethral and anal sphincters. Postmortem observations of the location of the M-Micro on the bladder wall were conducted after fixation. RESULTS: The animals' conditions were good. One animal was sacrificed early because of a skin infection. A single suture was sufficient to anchor the M-Micro. However, during the surgical implantation the pelvic plexus M-Micro ended up close to the bladder neck. Extensive fibrous connective tissue formed around the M-Micro and implanted catheters on the bladder wall. This appeared to result, in part, from multiple devices implanted on or near the bladder wall. CONCLUSIONS: These pilot studies showed that the M-Micro could be easily constructed and secured to the bladder wall or fat pads close to the pelvic plexus. There was a concern that the pelvic plexus location for the M-Micro ended near the bladder neck during the surgical implantation; however, these devices did not appear to migrate over this short, 3-month implantation period. The extensive connective tissue responses of the bladder wall to the tubes, wires, and M-Micro was a major concern. The M-Micro appears to be a good device to assess the potential of commercial microstimulators for use in micturition control.

Electrical stimulation for the treatment of bladder dysfunction: current status and future possibilities.

Electrical stimulation of peripheral nerves can be used to cause muscle contraction, to activate reflexes, and to modulate some functions of the central nervous system (neuromodulation). If applied to the spinal cord or nerves controlling the lower urinary tract, electrical stimulation can produce bladder or sphincter contraction, produce micturition, and can be applied as a medical treatment in cases of incontinence and urinary retention. This article first reviews the history of electrical stimulation applied for treatment of bladder dysfunction and then focuses on the implantable Finetech-Brindley stimulator to produce bladder emptying, and on external and implantable neuromodulation systems for treatment of incontinence. We conclude by summarizing some recent research efforts including: (a) combined sacral posterior and anterior sacral root stimulator implant (SPARSI), (b) selective stimulation of nerve fibers for selective detrusor activation by sacral ventral root stimulation, (c) microstimulation of the spinal cord, and (d) a newly proposed closed-loop bladder neuroprosthesis to treat incontinence caused by bladder overactivity.

Hypogastric plexus stimulators for obtaining semen from paraplegic men.

Radio-linked devices to stimulate the hypogastric plexus have been implanted into 7 patients with spinal injuries and 1 with primary anorgasmia. They caused seminal emission in all patients and still do so in the spinal injury patients. Insemination with semen thus obtained has yielded 5 pregnancies (2 live births) in the wives of 4 patients. The range of application is discussed.

Responses of neurons in nucleus ventralis posterolateralis of the cat thalamus' to hypogastric inputs.

Recordings were made from 68 units in the nucleus ventralis posterolateralis (VPL) of the cat thalamus, which responded to stimulation of hypogastric afferents. These units also received nociceptive inputs from the contralateral integument. Units which responded exclusively to hypogastric afferent inputs were not found. Thirty seven of the units were nociceptive specific (NS), and the remaining 31 were wide dynamic range (WDR) units. All of these units were located in the shell region of the lateral subdivision of the caudal VPL. NS units responding to hypogastric afferent inputs had a circumscribed cutaneous receptive field on the contralateral abdomen, gluteal region, tail or hind limb. These areas corresponded to tactile dermatomes T13-S2. Similarly, the cutaneous receptive fields of WDR units receiving hypogastric afferent inputs were distributed in the contralateral abdomen, gluteal region, tail and hind limb, with the sole exception of one unit, whose receptive field also included a part of the lower thorax. These findings extend the previous findings that the shell region of the caudal VPL of the cat thalamus constitutes a thalamic link in a visceral pain pathway, and that the visceral and cutaneous pathways share a common projection locus in the VPL.