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

项目总结 间质性膀胱炎/膀胱痛综合征(IC/BPS)是女性常见的慢性衰弱疾病。 IC/BPS的根本原因尚不清楚。我们最近发表了第一个功能性磁体 磁共振成像(FMRI)研究比较患有IC/BPS的女性和健康女性的脑功能。我们发现 IC/BPS患者辅助运动区(SMA)的静息活动发生改变。具体地说，这些 SMA的变化出现在我们已经展示的控制盆底肌肉活动的一部分(“骨盆SMA”)。我们的 结果为广泛发表的关于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一个关于慢性疼痛的重要理论的证据： 运动皮质的变化最初有益于增加保护性肌肉活动，但最终 适应不良和持久的疼痛。我们的目标是通过改善大脑活动和骨盆肌肉来减少疼痛 活动(使他们更接近健康的个体)。使用无创重复经颅磁 针对盆腔SMA的刺激(RTMS)，我们的目标是确定是否可以减轻疼痛(目标1)，改善休息 IC/BPS患者(目标2)的脑活动(FMRI)和静息盆底肌肉肌电(EMG)活动，以及 将疼痛减轻与fMRI/EMG改善联系起来，开发IC/BPS症状的因果调解模型 (目标3)。我们将招募75名患有IC/BPS的女性参与研究，参与者将被随机分配 对3组25名受试者测试不同的rTMS范式：高频(以增加兴奋性)、低频(以 降低兴奋性)和假(作为对照)。我们的初步数据表明，高频刺激 最好的方案，因为它改善休息骨盆SMA活动，同时减少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，该初步研究表明，5 与假刺激相比，连续几天的高频刺激可以减少IC/BPS疼痛，甚至测量到3 刺激停止后数周。我们会在拟议的工作中推广这些初步研究结果： 高频组和假rTMS组，我们将研究连续5天的刺激，两个较短的时间 结果衡量(与刺激的第一天有关)和长期结果衡量(3周 在刺激停止之后)。在低频rTMS组，我们将只检查较短的时间 与单次会议相关的结果衡量标准，因为我们的初步数据表明，低频 刺激是活跃的，但扰乱了盆底SMA和静息的盆底肌肉活动的价值 与健康对照有关，并不能减轻疼痛。我们的初步结果与大量的 文献表明，高频rTMS应用于运动皮质是减少rTMS的最佳范例 疼痛。然而，我们提出的工作有可能通过以下方式极大地创新治疗疼痛的大脑刺激领域 使用假的和积极的对照组，以及客观的fMRI/EMG结果测量，来定义 高频刺激改善慢性疼痛患者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.