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

与衰老相关的尿失禁机制中涉及的大脑机制的研究

• 批准号: 10425419
• 负责人: Becky D Clarkson
• 金额: $ 62.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10425419
• 关键词: Address; Age; Aging; Behavior Therapy; Behavioral; Benign; Biofeedback; Bladder; Bladder Control; Bladder Dysfunction; Brain; Brain imaging; Cerebrum; Clinical; Complement; Cross-Sectional Studies; Data; Development; Disease; Elderly; Failure; Functional Imaging; Goals; High Prevalence; Incidence; Incontinence; Individual; Investigation; Knowledge; Longevity; Machine Learning; Magnetic Resonance Imaging; Medial; Mediating; Micturition Reflex; Midbrain structure; Modeling; Neurosciences; Persons; Phenotype; Prefrontal Cortex; Premenopause; Process; Quality of life; Reaction; Refractory; Research Personnel; Resistance; Role; Scientist; Spasm; Structure; Therapeutic; Urge Incontinence; Urinary Incontinence; Woman; age group; age related; aged; analytical method; base; brain abnormalities; brain dysfunction; cohort; cost; improved; innovation; micturition urgency; mind control; neuroimaging; novel; novel therapeutics; predicting response; recruit; research clinical testing; response; side effect; targeted treatment; treatment response; young adult

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.

项目总结 大小便失禁是一个大问题，特别是对于老年人来说，大小便失禁非常普遍、病态和昂贵(2007年为660亿美元/年) 成人，其中最常见的类型是紧张性尿失禁(UUI)。一般归因于膀胱痉挛， UUI的实际原因尚不清楚，治疗仍然不足。最近的数据表明，一个原因是 大脑对膀胱的控制能力差。在我们最近的R01中，我们使用了生物反馈(BFB)作为一个探测器来探索这一点。这个 令人振奋的发现表明，老年人UUI的一种“表型”似乎是由 大脑控制，这可以通过成功的行为疗法恢复，而另一种是难以恢复的。我们的 拟议的新研究将进一步探讨这一点，试图通过区分与 疾病和衰老。目标是确定哪些大脑机制应该被抑制，因为它们 是导致或导致UUI的，应该加强这一点，因为他们帮助补偿 对于UUI，应该忽略它们，因为它们是随年龄增长的，并且与UUI无关。 目前的数据表明，膀胱控制包括3个大脑回路，通过以下方式维持控制 抑制中脑的排尿反射。在我们对BFB有反应的UUI表型中， 包括增强第一脑回路(内侧前额叶皮质，mPFC)的失活，从而导致 激活第二回路(包括中扣带皮质)。在抗性的表型中 BfB，未见脑部改变。 然而，尽管我们对大脑在UUI中的作用有了一个初步的了解，但我们对此只有初步的了解 什么是“正常”，即大脑通常是如何控制膀胱的。更重要的是，我们不知道 这种控制机制在整个寿命过程中是相同的，或者如果它因老化的影响而改变。 因此，我们的总体目标是描述年轻人和老年人的可控性，并研究如何 由于膀胱控制失败引起的变化在每个年龄段都不同。我们的具体目标是将正常 为了更好地了解和验证工作模式并在大陆老少咸宜地使用 与患有UUI的老年人进行比较，以了解这些人脑衰竭的机制。 为了达到这些目标，我们将对80例无症状患者进行详细的临床和神经影像研究。 女性和80名UUI女性，每组均分为青年(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，并确定参与 大小便控制、衰老引起的改变(良性的和促成UUI的)，以及疾病引起的改变。 这项研究将提供有关正常大小便的大脑机制的全面数据 机制，以便更好地证实我们的工作模型，了解老化过程，并评估 治疗的目标。因此，它将使科学家能够开发出新的、更有效的新疗法 关于神经科学的革命--给尿失禁患者带来了更多的希望。