Motor cortical neuromodulation in women with Interstitial Cystitis/Bladder Pain Syndrome: reducing pain by improving brain and muscle activity

项目摘要 间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是女性常见的慢性衰弱性疾病。 IC/BPS的根本原因仍不清楚。我们最近发表了第一个功能性磁 脑磁共振成像（fMRI）研究比较了IC/BPS女性与健康女性的脑功能。我们发现 患有IC/BPS的女性在补充运动区（SMA）的静息活动发生改变。具体来说，这些 SMA的一部分出现变化，我们已经证明其控制骨盆底肌肉活动（“骨盆-SMA”）。我们 结果为广泛发表的关于女性骨盆底肌肉活动增加的报道提供了第一个解释。 患有IC/BPS的女性我们假设我们正在观察慢性疼痛的一个重要理论的证据： 发生运动皮层变化，最初有利于增加保护性肌肉活动，但最终 适应不良并使痛苦永久化。我们的目标是通过改善大脑活动和骨盆肌肉来减轻疼痛 活动（使他们更像健康的人）。使用无创重复经颅磁共振 针对骨盆SMA的rTMS刺激，我们旨在确定我们是否可以减轻疼痛（目标1），改善休息 脑活动（fMRI）和静息骨盆底肌肉肌电图（EMG）活动在IC/BPS（目的2），并 将疼痛减轻与fMRI/EMG改善联系起来，以开发IC/BPS症状的因果中介模型 (Aim 3）。我们将招募75名患有IC/BPS的女性参与研究，参与者将被随机分组 3组，每组25人，以测试不同的rTMS模式：高频（以增加兴奋性），低频（以 降低兴奋性）和假手术（作为对照）。我们的初步数据表明，高频刺激是 最佳方案，因为它改善了静息骨盆SMA活动，同时减少了疼痛和骨盆肌肉活动。 这些结果与一项独立发表的初步研究一致，该研究表明， 连续几天的高频刺激可以减少IC/BPS疼痛相对于假手术，即使测量3 在停止刺激后几周。我们将在拟议的工作中扩展这些初步结果： 高频和假rTMS组，我们将研究连续5天的刺激与短期 结果测量（与刺激的第一天相关）和长期结果测量（3周 刺激停止后）。在低频rTMS组中，我们将只检查短期 结果的措施与一个单一的会议，因为我们的初步数据表明，低频率 刺激是主动的，但扰乱骨盆SMA和静息骨盆底肌肉活动，使其偏离值 与健康对照组相关，并且不会减轻疼痛。我们的初步结果与大量的 文献表明，高频rTMS应用于运动皮层是最好的rTMS范例，以减少 痛苦然而，我们提出的工作有可能极大地创新大脑刺激疼痛领域， 使用假手术和活性对照组，以及客观的fMRI/EMG结果测量，以定义 高频刺激可以改善慢性疼痛中运动功能缺陷的机制。

PROJECT SUMMARY Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a common, chronic, and debilitating condition in women. The underlying cause of IC/BPS remains unknown. We recently published the first functional magnetic resonance imaging (fMRI) study comparing brain function in women with IC/BPS to healthy women. We found that women with IC/BPS have altered resting activity in supplementary motor area (SMA). Specifically, these changes appear in a part of SMA that we have shown to control pelvic floor muscle activity (“pelvic-SMA”). Our results provide the first explanation for extensive published reports of increased pelvic floor muscle activity in women with IC/BPS. We hypothesize that we are observing evidence of an important theory of chronic pain: motor cortical changes occur that are initially beneficial to increase protective muscle activity but are ultimately maladaptive and perpetuate pain. Our goal is to reduce pain by improving brain activity and pelvic muscle activity (making them more similar to healthy individuals). Using non-invasive repetitive transcranial magnetic stimulation (rTMS) directed at pelvic-SMA, we aim to determine if we can reduce pain (Aim 1), improve resting brain activity (fMRI) and resting pelvic floor muscle electromyographic (EMG) activity in IC/BPS (Aim 2), and to link the pain reductions to fMRI/EMG improvements to develop a causal mediation model of IC/BPS symptoms (Aim 3). We will recruit 75 women with IC/BPS to participate in the study, and participants will be randomized to 3 groups of 25 to test different rTMS paradigms: high-frequency (to increase excitability), low-frequency (to decrease excitability), and sham (as a control). Our preliminary data suggest that high-frequency stimulation is the best protocol since it improves resting pelvic-SMA activity while reducing pain and pelvic muscle activity. These results are convergent with an independently-published preliminary study that suggests that 5 consecutive days of high-frequency stimulation can reduce IC/BPS pain relative to sham, even measured 3 weeks after the cessation of stimulation. We will extend these preliminary findings in the proposed work: in the high-frequency and sham rTMS groups, we will study 5 consecutive days of stimulation with both shorter-term outcome measures (associated with the first day of stimulation) and longer-term outcome measures (3 weeks after the cessation of stimulation). In the low-frequency rTMS group, we will only examine shorter-term outcome measures associated with a single session, since our preliminary data suggest that low-frequency stimulation is active but perturbs pelvic-SMA and resting pelvic floor muscle activity away from values associated with healthy controls and does not reduce pain. Our preliminary results agree with a large body of literature suggesting that high-frequency rTMS applied to motor cortex is the best rTMS paradigm to reduce pain. However, our proposed work has the potential to greatly innovate the field of brain stimulation for pain by using sham and active comparison groups, as well as objective fMRI/EMG outcome measures, to define the mechanism by which high-frequency stimulation can improve deficiencies in motor function in chronic pain.