Targeting urinary tract dysfunctions after spinal cord injury with epidural stimulation

（请保持文字，不要PDF） 摘要 脊髓硬膜外刺激（scES），它直接在脊髓上产生一个电场，已经显示出恢复脊髓损伤（SCI）患者下尿路（LUT）的自主和反射控制的早期希望。与Interstim系统和经皮入路相比，申报的多电极阵列的主要优势在于多电极的多功能性以及使用单个电极放置和器械同时激活多个结构和功能的能力。这项临床前研究的目标是优化scES的功能益处，并确定更好地促进日常管理和改善生活质量的机制。据推测，当SCI后慢性启动时，通过激活脊髓膀胱回路（包括背连合、背角浅部、骶副交感神经核和Onuf核内的神经元），需要完整的腹下/骨盆/阴部神经，发生膀胱储存和排空的有效scES，并且当与运动训练组合时具有更大的有效性。对于目标1，先前确定的最佳参数将用于确定脊髓网络的神经成分，其有助于使用两种方法在脊髓麻醉大鼠中的SCI后具有不同慢性的scES诱导的LUT效应：a）Fos蛋白诱导（脊髓神经元的突触后激活的标志物），和B）选择外周神经横断。检查用scES激活的脊髓中央区域和LUT功能的不同方面的关键外围组件，将为进一步开发和改进硬膜外阵列和控制器提供新的目标。对于目标2，将检查scES对用不同运动训练周期处理后的SCI大鼠中LUT功能的影响，以解决组合方法（神经调节与康复）的潜在附加益处。一个子目标是检查潜在的Fos诱导的中枢神经成分，因为可塑性可能是通过训练诱导的。两个目标还将包括慢性/训练影响的膀胱组织学/分子生物学评估。这些研究将通过为目标LUT功能提供最佳参数和位置来显着推动SCI领域的发展，这将是推进现有技术的关键。

(PLEASE KEEP IN WORD, DO NOT PDF) Abstract Spinal cord epidural stimulation (scES), which creates an electrical field directly over the spinal cord, has shown early promise for the restoration of voluntary and reflex control of the lower urinary tract (LUT) among individuals with spinal cord injuries (SCI). A major advantage of the proposed multi-electrode array over the Interstim system and transcutaneous approach is the versatility of the multi-electrode and the ability to activate multiple structures and functions simultaneously with a single electrode placement and device. The goal of this pre-clinical research is to optimize scES for functional benefits and identify mechanism(s) to better facilitate daily management and improve quality of life. It is hypothesized that effective scES for both bladder storage and emptying occurs when initiated chronically post-SCI through activation of spinal bladder circuits including neurons within the dorsal commissure, superficial dorsal horn, sacral parasympathetic nucleus, and Onuf’s nucleus, with the requirement of intact hypogastric/pelvic/pudendal nerves, and with greater effectiveness when given in combination with locomotor training. For Aim 1, previously identified optimal parameters will be used to identify neural components of the spinal networks contributing to scES-induced LUT effects with different chronicity’s post-SCI in urethane-anesthetized rats using two approaches: a) Fos protein induction (a marker for postsynaptic activation of spinal neurons), and b) select peripheral nerve transections. Examining the contributing spinal central regions activated with scES and key peripheral components for different aspects of LUT function will provide novel targets for further development and refinement of epidural arrays and controllers. For Aim 2, the impact of scES on LUT functions in SCI rats after treatment with differing periodicities of locomotor training will be examined to address the potential added benefit of a combinatory approach (neuromodulation with rehabilitation). A sub-aim examines the underlying Fos induced central neural components, as plasticity is likely induced with training. Both aims will also include bladder histology/molecular biology assessments re the effects of chronicity/training. These studies will significantly move the SCI field forward by providing optimal parameters and locations for targeting LUT function that will be key for advancing the existing technology.