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.

项目概要 失禁是一个普遍存在、病态且代价高昂的主要问题（2007 年为每年 660 亿美元），尤其是对于老年人来说 成人中，最常见的类型是急迫性尿失禁（UUI）。一般归因于膀胱痉挛， UUI 的真正原因尚不清楚，治疗方法仍然不充分。最近的数据表明，原因之一是 大脑对膀胱的控制不良。在我们最近的 R01 中，我们使用生物反馈（BFB）作为探针来探索这一点。这 令人兴奋的发现表明，老年人 UUI 的一种“表型”似乎是由 大脑控制，可以通过成功的行为疗法来恢复，而另一种则是难以控制的。我们的 拟议的新研究将通过尝试区分与相关的机制来进一步探讨这一点 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 有助于或导致 UUI，应该加强 UUI，因为它们有助于补偿 对于 UUI，应该忽略它们，因为它们是老化附带的且与 UUI 无关。 目前的数据表明，膀胱控制由 3 个大脑回路组成，它们通过以下方式维持节制： 抑制中脑的排尿反射。在我们对 BFB 做出反应的 UUI 表型中，该机制 涉及增强第一大脑回路（内侧前额叶皮层，mPFC）的失活，从而减少 第二个回路（包括中扣带皮层）的激活。在具有抗性的表型中 BFB，没有看到大脑变化。 然而，尽管我们对大脑在 UUI 中的作用有了初步了解，但我们还只有初步的了解 什么是“正常”，即大脑通常如何控制膀胱。比较相关，不知道是否 这种控制机制在整个生命周期中都是相同的，或者是否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失禁控制特征，并研究如何 由于膀胱控制失败而导致的变化在每个年龄组中都不同。我们的具体目标是表征正常 为了更好地理解和验证工作模式并使用 与患有 UUI 的老年人进行比较，以了解这些人脑衰竭的机制。 为了实现这些目标，我们将进行详细的临床和神经影像学研究，以研究 80 名无症状患者 女性和 80 名 UUI 女性，每组均分为年轻（18-45 岁）和老年（65 岁以上）。该研究将 使我们能够评估大脑结构和功能的变化，并确定参与的大脑机制 失禁控制、衰老引起的变化（良性的和导致 UUI 的）以及疾病引起的变化。 该研究将提供有关正常失禁的大脑机制的全面数据 机制，以便更好地验证我们的工作模式、了解老化过程并评估 治疗的目标。从而使科学家能够开发出新颖且更有效的新疗法 神经科学的革命——以及 UUI 患者的更多希望。