Investigation of brain mechanisms involved in the Urinary Continence mechanism associated with aging

项目摘要 尿失禁是一个普遍的、病态的和昂贵的问题（2007年为660亿美元/年），特别是对于老年人来说 成人，其中最常见的类型是急迫性尿失禁（UUI）。一般认为是膀胱痉挛， 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，老年人UUI的一种“表型”似乎是由以下因素引起的： 大脑控制，这可以通过成功的行为治疗恢复，而另一个是顽固的。我们 拟议的新研究将进一步探索这一点，试图区分与 疾病和衰老。目的是确定哪些大脑机制应该被抑制，因为它们 导致或导致UUI，这应该得到加强，因为它们有助于补偿 对于UUI，应忽略，因为它们是老化的附带结果，与UUI无关。 目前的数据表明，膀胱控制包括3个大脑回路， 抑制中脑的排尿反射在我们对BFB有反应的UUI表型中， 涉及加强第一个大脑回路（内侧前额叶皮层，mPFC）的失活，这导致 激活第二回路（包括中扣带回皮质）。在抵抗的表型中， BFB，未观察到脑变化。 然而，尽管我们对大脑在UUI中的作用有了初步的了解， 什么是“正常”，即大脑通常如何控制膀胱。更重要的是，我们不知道是否 这种控制机制在整个生命周期中是相同的，或者如果它由于衰老的影响而发生变化。 因此，我们的总体目标是描述年轻人和老年人的情绪控制，并研究他们如何控制情绪。 由于膀胱控制失败的变化在每个年龄组中不同。我们的具体目标是描述正常的 为了更好地理解和验证工作模型， 与患有UUI的老年人进行比较，以了解这些人脑功能衰竭的机制。 为了实现这些目标，我们将进行详细的临床和神经影像学研究，研究80例无症状 妇女和80名UUI妇女，每组平均分为青年（18-45岁）和老年（65岁以上）。这项研究将 使我们能够评估大脑结构和功能的变化，并确定大脑机制参与 年龄控制、因老化引起的变化（良性和促成UUI）以及因疾病引起的变化。 这项研究将提供有关正常大脑活动的大脑机制的全面数据。 为了更好地证实我们的工作模型，了解衰老过程， 治疗的目标这将使科学家能够开发出新的，更有效的新疗法， 神经科学的革命，以及UUI患者的更多希望。

PROJECT SUMMARY Prevalent, morbid, and costly ($66 billion/year in 2007), incontinence is a major problem, especially for older adults, in whom the most common type is urgency incontinence (UUI). Generally 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 one `phenotype' of UUI in older adults seems to be caused by a breakdown in brain control, which can be restored by successful behavioral therapy, while another is refractory. Our proposed new study will explore this further by attempting to differentiate the mechanisms associated with disease and aging. The goal is to identify which brain mechanisms should be suppressed because they are contributing to or causing UUI, which should be enhanced because they are helping to compensate for UUI, and which should be ignored because they are incidental to aging and not related to UUI. Current data suggest that bladder control comprises 3 cerebral circuits that maintain continence by suppressing the voiding reflex in the midbrain. In our UUI 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, although we have an emerging picture of the brain's role in UUI, we have only rudimentary understanding of what is `normal', i.e. how the brain normally controls the bladder. More relevant, we do not know whether this control mechanism is the same across the lifespan, or if it changes owing to the impact of aging. Thus, our overall aim is to characterize continence control in both young and old people, and examine how changes due to bladder control failure differ in each age group. Our specific aims are to characterize normal voiding in the continent old and young in order to better understand and verify the working model and to use the comparison to older adults with UUI to understand the mechanism of brain failure in these individuals. To address these aims, we will conduct a detailed clinical and neuroimaging study to study 80 asymptomatic women and 80 UUI women, each group divided equally into young (18-45) and old (65+ years). The study will enable us to evaluate the changes in brain structure and function and to identify brain mechanisms involved in continence control, changes due to aging (both benign and contributory to UUI), and changes due to disease. The study will provide the comprehensive data on brain mechanisms involved in the normal continence mechanism in order to better corroborate our working model, understand the aging process, and assess targets for therapy. It will thereby enable scientists to develop novel and more effective new therapies based on the revolution in neuroscience—and more hope for UUI sufferers.