Central Sensitization and Psychosocial Impacts on Overactive Bladder

项目总结 非神经源性膀胱过度活动(OAB)(即尿急，伴或不伴尿失禁， 频率和夜尿症)影响七分之一的美国男性和女性。它可能很难有效地治疗，而且目前 这种方法是一刀切的，反复试验，很大程度上是因为OAB的病因尚不清楚。一个 大量动物和体外研究表明传入活动增加和中枢神经系统改变 OAB病理生理学中兴奋性信号的处理，导致膀胱过敏。然而， 可能反映膀胱过敏状态的临床特征识别较差，因此 基于传入病理生理机制的OAB表型，这对个体化至关重要 OAB的护理，仍然难以捉摸。作为回应，我们假设中枢敏化(CS)是一种 某些个体OAB的病理生理机制，这可能解释了膀胱 OAB中提出的超敏反应。从我们的初步工作中发现的时间升高 女性OAB的疼痛总和(即以定量感觉测试(TSP)为指标的CS的主要标志) 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 这可能与患有OAB的男性有关。因此，我们现在提出CS不仅对膀胱有贡献 对心理社会负担的敏感性，特别是增加了负面情绪(这是一个常见的发现 这两个人都患有CS介导的疾病和OAB)，然后影响膀胱症状。我们将对此进行测试 假设有200名患有OAB的男性和女性，以及60名非OAB对照，使用一种高度创新的 跨学科方法。目标1确定OAB中CS的表型特征，包括 中枢感觉敏感度、心理社会因素升高、慢性疼痛状况的共同发病率，以及更大的 尿路症状。由于CS与OAB的联系以前没有在男性身上进行过检查，我们将进行性行为测试 CS相关表型的差异。目标2将首次直接测试CS对膀胱的影响 OAB中的灵敏度。目标3将考察CS是否缓和日常负面情感影响 OAB症状使用最先进的生态学瞬时评估方法。完成后，我们将 期望能够识别具有基于机制的表型(CS相关的OAB)的OAB个体 首次通过签名机制和表型特征进行了分析。我们预计患有这种CS的人- OAB关联，可能是因为高心理社会影响和CS介导的过敏症，将会有更多 很难使用标准的OAB干预措施(即OAB药物)进行治疗，可能需要多模式或 高级治疗。这将通过未来的干预研究进行评估，以衡量个性化的OAB 基于潜在的CS机制的治疗结果，并确定这种OAB-CS关联的因果关系， 这将有助于开启精准医学时代，优化OAB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.