Central Sensitization and Psychosocial Impacts on Overactive Bladder

项目摘要 非神经源性膀胱过度活动症（OAB）（即尿急，伴有或不伴有尿急性尿失禁， 频率，和糖尿病）影响1/7的美国男性和女性。很难有效治疗，目前 这种方法是一种通用的、反复试验的方法，这在很大程度上是因为OAB的病因尚不清楚。一 大量动物和离体研究表明，传入活动增加，CNS改变 OAB病理生理学中兴奋性信号的处理，导致膀胱超敏反应。然而，在这方面， 可能反映膀胱超敏状态的临床特征识别不佳， 基于传入病理生理机制的表型OAB，这对于个体化治疗至关重要。 OAB护理，仍然难以捉摸。作为回应，我们假设中枢致敏（CS）是一种 某些个体中OAB的病理生理机制，这可能解释膀胱 OAB中提出的超敏反应。我们的初步研究结果表明， 女性OAB的疼痛总和（即定量感觉测试，TSP索引的CS的主要标志物） 患者似乎支持这一点。然而，我们仍然对CS在OAB中的表现知之甚少，包括如何 这可能与OAB男性有关。因此，我们现在提出，CS不仅有助于膀胱 敏感性，但也对心理社会负担，特别是增加负面影响（这是一个常见的发现 患有CS介导的病症和OAB的个体），然后影响膀胱症状。我们将测试这个 假设样本为200名男性和女性OAB和60名非OAB对照，使用高度创新， 跨学科方法。目的1确定OAB中CS的表型特征，包括更大的 中枢感觉敏感性，心理社会因素升高，与慢性疼痛病症共病，以及更大 泌尿系统症状因为CS与OAB的联系以前没有在男性中进行过研究，我们将进行性别测试 CS相关表型的差异。目的2将首次直接测试CS对膀胱的影响 OAB的敏感性。目标3将检验CS是否缓和了日常的负面情感影响， OAB症状使用最先进的生态瞬时评估方法。完成后，我们 预期能够识别具有定义的基于机制的表型（CS相关OAB）的OAB个体 通过签名机制和表型特征的第一次。我们预计有这种症状的人- OAB相关性，可能是因为高心理社会影响和CS介导的超敏反应，将更多 使用标准OAB干预（即OAB药物）难以治疗，可能需要多模式或 先进的治疗这将在未来的干预研究中进行评估，以衡量个性化的OAB 基于潜在CS机制的治疗结局，并确定OAB-CS相关性的因果关系， 这将有助于开创一个精确医学的时代，以优化对患有OAB的男性和女性的护理。

PROJECT SUMMARY Non-neurogenic overactive bladder (OAB) (i.e. urinary urgency, with or without urgency urinary incontinence, frequency, and nocturia) affects 1 in 7 U.S. men and women. It can be difficult to treat effectively, and the present approach is one-size-fits-all, trial-and-error, in large part because the etiology of OAB remains unclear. A substantive body of animal and ex vivo research implicates increased afferent activity and altered CNS processing of excitatory signals in OAB pathophysiology, contributing to bladder hypersensitivity. However, clinical characteristics that may reflect a bladder hypersensitivity state are poorly recognized and thus phenotyping OAB based on afferent pathophysiologic mechanisms, which would be crucial for individualized OAB care, has remained elusive. In response, we hypothesize that central sensitization (CS) is a pathophysiologic mechanism underlying OAB in certain individuals, which might explain the bladder hypersensitivity proposed in OAB. Findings from our preliminary work demonstrating elevated temporal summation to pain (i.e. primary marker for CS indexed with quantitative sensory testing, TSP) in female OAB patients appear to support this. Yet, we still know very little about how CS manifests in OAB, including how relevant it may be for men with OAB. Therefore, we now propose that CS not only contributes to bladder sensitivity, but also to psychosocial burdens, specifically increased negative affect (which is a frequent finding both individuals with CS-mediated conditions and OAB), which then impacts bladder symptoms. We will test this hypothesis with a sample of 200 men and women with OAB and 60 non-OAB controls, using a highly innovative, interdisciplinary approach. Aim 1 identifies phenotypic features characteristic of CS in OAB, including greater central sensory sensitivity, elevated psychosocial factors, co-morbidity with chronic pain conditions, and greater urinary symptoms. Because CS links to OAB have not previously been examined in men, we will test for sex differences in CS-related phenotypes. Aim 2 will directly test, for the first time, the effects of CS on bladder sensitivity in OAB. Aim 3 will examine whether CS moderates the day-to-day negative affective influences on OAB symptoms using a state-of-the-art ecological momentary assessment approach. When completed, we expect to be able to identify OAB individuals with a mechanism-based phenotype (CS-associated OAB) defined by signature mechanistic and phenotypic features for the first time. We anticipate that individuals with this CS- OAB association, likely because of the high psychosocial impact and CS-mediated hypersensitivity, will be more difficult to treat using standard OAB interventions (i.e. OAB medications) and may require multimodal or advanced therapy. This will be assessed with future intervention studies to measure individualized OAB treatment outcomes based on underlying CS mechanisms and determine causality of this OAB-CS association, which will help usher in an era of precision medicine to optimize care of men and women with OAB.