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

描述（由申请人提供）：便秘影响高达20%的美国人口，主要是女性和老年人。受影响的个体生活质量受损，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潜在的多因素功能障碍的疗法，并阐明其神经生物学和机制基础。通过之前的应用，我们发现生物反馈改善了排便失调，并导致了更高的患者满意度。在这里，我们的目标是测试其他功能障碍的新行为治疗方法，并通过将其与机制研究相结合，我们可以揭示大脑和肠道（肠-脑轴）如何相互作用，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，生物反馈疗法需要熟练的治疗师在生理实验室中使用复杂的设备来训练患者。我们开发并测试了一种电池供电的设备，供病人在自己家里使用。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同样有效。我们将调查和比较100例排便失调患者的疗效、成本和结果，随机分为家庭治疗和办公室治疗两组。2)我们的初步研究表明，与对照组相比，协同失调患者的肠-脑功能紊乱，生物反馈可恢复正常功能。我们将通过测量电刺激肛门直肠（传入）后的皮质诱发电位（CEP）和经颅磁刺激（传出）后的运动诱发电位（MEP），研究50名失协同受试者（生物反馈前后）的肛门直肠-脑相互作用的完整性，并与25名健康对照进行比较。3)目前，低敏感性直肠的感觉调节包括用手持注射器反复填充气球；这种笨拙的方法降低了它的有效性。我们将在一项随机研究中测试，在70例直肠低敏的便秘受试者中，是否气压计（压力驱动的计算机系统）训练优于注射器辅助的感觉训练。此外，我们将通过研究直肠感觉运动功能以及感觉训练前后的cep和mep来研究直肠低敏感性的神经肠机制，并阐明神经元调节的位点（中枢与外周）。便秘并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，包括使用压力调节器的感觉适应训练（SAT）。在一项随机对照试验中，我们将在60例便秘IBS患者中比较SAT和escitalopram（一种SSRI），并测试其在减轻疼痛和改善过敏反应方面的疗效。这些研究的目的是确定机制，并评估新的治疗方法的协同作用障碍，直肠低敏和直肠超敏，并可能显著影响便秘的治疗。

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.