Targeting urinary tract dysfunctions after spinal cord injury with epidural stimulation

(请保存在Word中，不要保存为PDF) 摘要 脊髓硬膜外刺激(SCES)直接在脊髓上产生电场，在脊髓损伤(SCI)患者中恢复下尿路(LUT)的自主反射控制已显示出早期的前景。与Interstim系统和经皮途径相比，所提出的多电极阵列的主要优势是多电极的多功能性以及通过单个电极放置和装置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，并确定机制(S)，以更好地促进日常管理，提高生活质量。据推测，脊髓损伤后通过激活脊髓回路，包括后连合、浅背角、腰交感神经核和Onuf核内的神经元，在需要完整的腹下/盆腔/阴部神经的情况下，发生有效的膀胱储存和排空的SCES，并在结合运动训练时具有更好的效果。对于目标1，先前确定的最佳参数将被用来通过两种方法在乌拉坦麻醉的大鼠脊髓损伤后识别参与SCES诱导的LUT效应的脊髓网络的神经成分：a)Fos蛋白诱导(脊髓神经元突触后激活的标志)，以及b)选择周围神经横断。研究SCES激活的脊髓中央区域和LUT功能不同方面的关键外周成分将为进一步开发和改进硬膜外阵列和控制器提供新的靶点。对于目标2，SCES对不同运动训练周期的SCI大鼠的LUT功能的影响将被检测，以解决组合方法(神经调节和康复)的潜在额外好处。一个子目标是检查潜在的Fos诱导的中枢神经成分，因为可塑性很可能是通过训练诱导的。这两个目标还将包括膀胱组织学/分子生物学评估和慢性化/训练的影响。这些研究将通过提供针对LUT功能的最佳参数和位置来显著推动SCI领域的发展，LUT功能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.