Electrical Stimulation Facilitation of Recovery from Childbirth Injury

描述:

DESCRIPTION: Urinary incontinence, particularly stress urinary incontinence (SUI), is common and very bothersome among female veterans. Although not life threatening, SUI greatly reduces quality of life and, among female veterans is significantly correlated with a history of depression and sexual assault. SUI is also strongly correlated with vaginal delivery of children, which can injure the muscles, and organs of the pelvic floor, including the external urethral sphincter (EUS). In addition, the pudendal nerve, which innervates the EUS, can be injured in Alcock's canal during delivery, proximal to its innervations of the urethra. Thus, the injuries incurred during childbirt represent a unique neuromuscular injury: one in which both the target muscle (the EUS) and its innervation are injured simultaneously. These two injuries, along with injuries to the tissues and muscles of the pelvic floor are strongly correlated with later development of SUI. Brain-derived neurotrophic factor (BDNF) must be produced by the target muscle to regenerate motoneurons and reinnervate the muscle after peripheral nerve injury. However, if muscle is injured, BDNF inhibits neuromuscular junction (NMJ) repair. Therefore, when both a nerve and its innervated muscle are injured, as can occur during childbirth, BDNF downregulation by the muscle inhibits nerve regeneration. We have developed a novel animal model of simulated childbirth injury and have demonstrated that a neurotrophin- mediated mechanism could be responsible for delayed and possibly incomplete neuroregeneration after vaginal delivery. Electrical stimulation (e-stim) increases BDNF expression in injured neurons and promotes nerve regeneration. It may present an alternative therapy with fewer complications than treatment with BDNF. E-stim therapy to promote nerve regeneration has had mixed success, in part because it has only been utilized after nerve injury, not after a combination nerve and muscle injury, as can occur in childbirth. Precisely because of this, investigation of the mechanism of action of e-stim after a combinatorial nerve and muscle injury in a specific clinically related model is crucial for optimizing the therapy and the patient subpopulation to treat. We have recent data that e-stim of the pudendal nerve after simulated childbirth injury upregulates BDNF in pudendal nerve cells and promotes functional recovery of the urethra. However, this data is correlative rather than causative. Therefore, the hypothesis to be tested in this project is that e- stim improves recovery from simulated childbirth injury via a BDNF-mediated mechanism. This hypothesis will be tested via the following specific objectives (SO): SO1. Optimize an e-stim paradigm for improvement of recovery after simulated childbirth injury; SO2. Demonstrate that accelerated recovery of function with e- stim correlates with chronic improvement; SO3. Demonstrate that BDNF is necessary and sufficient for spontaneous recovery after pudendal nerve crush (PNC) and accelerated recovery with supplemental BDNF after simulated childbirth injury. SO4. Demonstrate that e-stim facilitates recovery from simulated childbirth injury via a BDNF-mediated mechanism. This project will provide critical pre-clinical data to initiate a clinical tril to assess e-stim as an adjuvant to rehabilitation for female veterans with SUI. Approximately 1/3 of women have postpartum SUI following delivery. Although this resolves in most women, almost half of these women redevelop it 5 years later and over half redevelop it years later, indicating that postpartum SUI is predictive of later SUI. Women with postpartum SUI could constitute the population for a clinical trial of e- stim, which could treat their current incontinence and preven redevelopment of SUI. This research directly relates to the Rehabilitation R&D Priority Area of Aging. In addition, women are the fastest growing segment of the veteran population, representing 14% of active duty forces and 20% of new military recruits, and are a priority for the VA research program. Since incontinence and depression are so closely correlated among female veterans, improvement of incontinence symptoms may help lead to recovery from depression.