Novel Treatment Strategies for Constipation and Role of Brain-Gut axis

描述(申请人提供)：便秘影响多达20%的美国人口，主要是妇女和老年人。受影响的个人生活质量受损，大多数人对目前的治疗不满意。我们的长期目标是开发治疗方法，纠正潜在的多因素功能障碍(S)，并阐明其神经生物学和机制基础。通过先前的应用，我们表明生物反馈改善了排便功能失调，并导致了患者更高的满意度。在这里，我们的目标是测试针对其他功能障碍的新的行为治疗方法，通过将其与机制研究相结合，我们可以揭示大脑和肠道(肠道-脑轴)是如何相互作用的，以及生物反馈如何调节皮质-直肠功能。我们提出了四个具体目标：1)目前，生物反馈疗法需要一名熟练的治疗师在生理实验室使用复杂的设备对患者进行培训。我们开发并测试了一种电池供电的设备，供患者在自己的家中使用。我们将确定基于社区的生物反馈疗法是否与基于实验室的生物反馈疗法一样有效。我们将调查和比较100名排便不协调的患者的疗效、成本和结果，这些患者随机分为家庭治疗和办公室治疗。2)我们的初步研究表明，与对照组相比，协同障碍患者的肠脑功能紊乱，生物反馈恢复了正常功能。我们将通过测量电刺激肛门直肠(传入)后的皮层诱发电位(CEP)和经颅磁刺激(传出)后的运动诱发电位(MEP)，来研究50名协同障碍受试者(生物反馈前后)肛门直肠-脑相互作用的完整性，并与25名健康对照组进行比较。3)目前，直肠感觉条件反射涉及用手持注射器反复填充气囊；这种笨拙的方法降低了其有效性。我们将在一项随机研究中，在70名直肠低敏感性便秘受试者中测试恒压(压力驱动的计算机系统)训练是否优于注射器辅助的感觉训练。此外，我们还将通过研究感觉训练前后的肛门直肠感觉运动功能以及CEP和MEP来探讨直肠感觉低下的神经肠道机制(S)，并阐明神经调节的位置(中枢与外周)。4)便秘伴腹痛通常与直肠过敏有关，这种情况没有有效的治疗方法。我们开发并测试了一种新的行为疗法，包括使用恒压计进行感觉适应训练(SAT)。在随机对照试验中，我们将在60名便秘IBS患者中将SAT与SSRI艾司西妥普兰进行比较，并测试其在减轻疼痛和改善过敏方面的疗效。这些研究旨在明确协同失调、直肠感觉不灵敏和直肠超敏的机制，并评估新的治疗方法，这些研究可能对便秘的治疗产生重大影响。

DESCRIPTION (provided by applicant): Constipation affects up to 20% of the US population, mainly women and the elderly. Affected individuals experience impaired quality of life and most are dissatisfied with current therapy. Our long-term goals are to develop therapies that remedy the underlying multifactorial dysfunction(s), and elucidate their neurobiologic and mechanistic bases. Through the previous application, we showed that biofeedback improved dyssynergic defecation and led to superior patient satisfaction. Here we aim to test new behavioral treatments for other dysfunctions and by integrating this with mechanistic studies we can reveal how the brain and the gut (gut- brain axis) interact, and how biofeedback modulates cortico-rectal function. We propose four specific aims: 1) Currently, biofeedback therapy requires a skilled therapist to train a patient using sophisticated equipment in a physiologic laboratory. We developed and tested a battery powered device for patients to use in their own home. We will determine if a community-based biofeedback therapy is as effective as laboratory- based biofeedback therapy. We will investigate and compare the efficacy, costs and outcomes of 100 patients with dyssynergic defecation, randomized to either home therapy or office-based therapy. 2) Our preliminary studies revealed that gut-brain function is deranged in dyssynergic patients, compared to controls and that biofeedback restores normal function. We will investigate the integrity of anorectal-brain interactions in 50 dyssynergic subjects (before and after biofeedback) and compare this with 25 healthy controls by measuring the cortical evoked potentials (CEP) after electrical stimulation of the anorectum (afferent) and the motor evoked potentials (MEP) following transcranial magnetic stimulation (efferent). 3) Currently, sensory conditioning of a hyposensitive rectum involves repetetive filling of a balloon with a hand-held syringe; this awkward approach reduces its effectiveness. We will test, in a randomized study, if barostat (pressure-driven computerized system) training is superior to syringe-assisted sensory training, in 70 constipated subjects with rectal hyposensitivity. Also, we will examine the neuroenteric mechanism(s) of rectal hyposensitivity by investigating anorectal sensori-motor function as well as CEPs and MEPs, before and after sensory training, and elucidate the locus (central versus peripheral) for neuronal modulation. 4) Constipation accompanied by abdominal pain is commonly associated with rectal hypersensitivity, a condition with no effective therapy. We developed and tested a new behavioral therapy, comprising of sensory adaptation training (SAT) using a barostat. In a RCT, we will compare SAT with escitalopram, a SSRI, in 60 constipated IBS patients and test its efficacy in reducing pain and improving hypersensitivity. These studies aim to define the mechanisms of, and evaluate new therapies for dyssynergia, rectal hyposensitivity and rectal hypersensitivity, and could significantly impact constipation treatments.