Investigation of brain mechanisms involved in Urgency Urinary Incontinence

项目摘要 尿失禁是一个普遍的、病态的和昂贵的问题（2000年超过200亿美元/年），特别是对于老年人来说， 成人，其中最常见的类型是紧急尿失禁（UUI）。归因于膀胱痉挛， UUI的真正原因尚不清楚，治疗仍然不足。最近的数据表明，原因之一是 大脑对膀胱的控制能力很差在我们最近的R 01中，我们使用生物反馈（BFB）作为探针来探索这一点。的 令人兴奋的发现表明，有≥ 2种脑（表型）类型的UUI;它们对BFB的反应不同， 通过不同的机制;他们的反应可以预测。我们提出的新研究将扩大这一点， 研究药物治疗的机制，以确定潜在的新的治疗目标。 数据表明，膀胱控制包括3个大脑回路，通过抑制 中脑的排泄反射在对BFB有反应的表型中，其机制涉及增强 第一个大脑回路（内侧前额叶皮层，mPFC）的失活，导致大脑皮层的激活减少。 第二回路（包括中扣带皮层）。在对BFB耐药的表型中，没有脑 看到了变化。 然而，BFB的使用频率低于治疗UUI的药物。介导药物反应的机制是 未知，但可能涉及传入活动上升到大脑的变化。拟议的研究将是 第一个解决这一关键知识差距的国家。它不仅基于我们的BFB研究产生的见解， 而且还对膀胱松弛剂非索罗定和我们的大脑/膀胱控制工作模型进行了初步研究。 我们的总体目标是将非索特罗定用作生理探针，以提高我们对大脑作用的理解。 并确定新的治疗靶点。具体目的是：（1）检测药物治疗的疗效是否存在差异 通过大脑表型（我们的BFB研究中确定的两种或本研究将确定的其他表型）;（2）证实， mPFC失活是一个关键的治疗机制，无论干预;（3）确定是否药物治疗 使大脑反应正常化，作为对治疗的非特异性反应;以及（4）使用更新的MRI技术来扩展 我们目前的方法，从而证实或反驳我们的大脑/膀胱控制模型。 为了实现这些目标，我们将随机选择150名年龄≥ 60岁的女性接受12周的fesoter- odine或安慰剂，然后将他们转换为另一种治疗12周。这项研究将使我们 将CNS激活/失活的变化与对治疗的临床反应相关联， CNS变化是否在停止治疗（安慰剂）后恢复为失禁， 识别大脑预测因子和反应机制。 这项研究将提供有关UUI对药物反应的大脑机制的第一批数据。无论 结果，它将大大有助于目前对UUI和UUI的理解，从而使科学， 他们试图在神经科学革命的基础上开发新的治疗方法，这给UUI患者带来了更多的希望。

PROJECT SUMMARY Prevalent, morbid, and costly (>$20 billion/year in 2000), incontinence is a major problem, especially for older adults, in whom the most common type is urgency urinary incontinence (UUI). Ascribed to bladder spasms, UUI's actual causes are unknown, and therapy remains inadequate. Recent data suggest that one cause is poor bladder control by the brain. In our recent R01 we used biofeedback (BFB) as a probe to explore this. The exciting findings suggest that there are ≥ 2 brain (pheno)types of UUI; that they respond differently to BFB, and via different mechanisms; and that their response can be predicted. Our proposed new study will extend this work to examine mechanisms of drug treatments to identify potentially new targets for therapy. Data suggest that bladder control comprises 3 cerebral circuits which maintain continence by suppressing the voiding reflex in the midbrain. In the phenotype that responded to BFB, the mechanism involved enhancing deactivation of the first brain circuit (medial prefrontal cortex, mPFC) which resulted in less activation of the second circuit (which includes the midcingulate cortex). In the phenotype that was resistant to BFB, no brain changes were seen. Yet, BFB is used less often than drugs to treat UUI. The mechanism(s) that mediate drug response are unknown but likely involve changes in afferent activity ascending to the brain. The proposed study would be the first to address this critical knowledge gap. It is based not only on insights generated from our BFB study, but also on a pilot study of the bladder relaxant fesoterodine and our working model of brain/bladder control. Our overall aim is to use fesoterodine as a physiological probe, to improve our understanding of the brain's role in UUI and identify new targets for therapy. Specific aims are to: (1) test whether efficacy of drug therapy varies by brain phenotype (the two identified in our BFB study or others that this study will identify); (2) confirm that mPFC deactivation is a key therapeutic mechanism, regardless of intervention; (3) determine if drug therapy normalizes brain response as a non-specific reaction to therapy; and (4) use newer MRI techniques to extend our current methods and thereby confirm or refute our model of brain/bladder control. To address these aims, we will randomize 150 women aged ≥ 60 years to receive 12 weeks of either fesoter- odine or placebo and then switch them to the alternate therapy for another 12 weeks. The study will enable us to correlate the change in CNS activation/deactivation with clinical response to therapy and also to discern whether CNS changes revert as incontinence worsens following withdrawal of therapy (on placebo) and to identify brain predictors and mechanisms of response. The study will provide the first data on brain mechanisms involved in UUI response to a drug. Regardless of results, it will contribute substantially to current understanding of UUI and continence, thereby enabling scien- tists to develop new therapies based on the revolution in neuroscience—and more hope for UUI sufferers.