Optimization of Non Invasive Brain Stimulation for Diabetic Neuropathic Pain

抽象的。糖尿病神经病理性疼痛(DNP)是糖尿病最常见和最难治疗的并发症之一 糖尿病[1，2]。目前的疗法[3-10]并没有直接解决这样一个事实，即痛感是在 大脑[10-13]，大多数发生在神经病变部位(即，外围)，尽管DNP患者也有 中枢性疼痛成分，因其受伤[10-13]。DNP症状与慢性疼痛相关 大脑活动和/或结构的变化[13-19]。非侵入性脑刺激(NIBS)已经成功 用于治疗某些疾病状态下的慢性疼痛，治疗会引起大脑的变化 活动逆转了与慢性疼痛的知觉/感觉相关的适应不良可塑性[20-23]。然而， 最常用的NIBS方法有经颅磁刺激(TMS)和经颅直流电 刺激(TDCs)，在治疗神经病理性疼痛和DNP方面显示出有限的疗效[12，24-30]。它有 据推测，这些技术在聚焦、穿透和目标控制方面的限制限制了它们 疗效[31-35]。电声刺激(ESSTim™)是一种改进的NIBS模式，它克服了 独立控制的电磁和超声波相结合的其他技术的局限性 通过神经组织中的可调谐机电耦合聚焦和增强刺激电流的场[36]。这 提案的重点是评估我们的非侵入性ESSTim系统是否可以有效地治疗DNP。先入 第一阶段，为了评估拟议工作的可行性，我们将在给药固定剂量后跟踪20名DNP患者。 连续5天，20分钟/天(10个假ESSTim，10个ESSTim™)。我们将管理一个电池 安全、疼痛、定量感觉测试(QST)、运动功能和全球自我评估(例如，QOL)， 在治疗期间和至少六周内对患者的运动测量进行评估 在最后一次治疗之后。接下来，在第二阶段，我们将跟踪40名DNP患者(20名ESSTim，20名Sham) 在给予固定剂量的刺激后，连续5天，每天20分钟，然后是三周的两次- 每周刺激，20分钟/天(共11次刺激)。我们将用相同的电池评估这些患者 在第一阶段验证的评估，并比较至少八周内测试干预措施的有效性 在最后一次治疗之后。在DNP治疗的同时，我们将建立磁共振成像衍生模型 DNP患者头部刺激场(电场和声场模型)计算 脑靶部位刺激场特征。多元线性回归和广义线性回归 然后将建立和评估模型，以预测DNP患者与疼痛、身体功能、 以及心理社会评估作为基线疾病特征和基于MRI的剂量的函数 模特们。计算工作将结合起来，开发一个优化的DNP ESSTim剂量模型。总的来说， 我们假设，拟议的实验、计算研究和技术开发将允许 美国优化ESSTim™治疗中枢性疼痛。

Abstract. Diabetic neuropathic pain (DNP) is one of the most common and difficult to treat complications of diabetes [1, 2]. Current therapies [3-10] do not directly address the fact that pain sensation is processed in the brain [10-13] and most act at the neuropathy site (i.e., in the periphery), although DNP patients also have a central pain component due to their injury [10-13]. DNP symptomatology correlates with chronic pain induced changes in brain activity and/or structure [13-19]. Non-Invasive Brain Stimulation (NIBS) has been successfully applied for the treatment of chronic pain in some disease states, where treatment induced changes in brain activity revert maladaptive plasticity associated with the perception/sensation of chronic pain [20-23]. However, the most common NIBS methods, Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), have shown limited, if any, efficacy in treating neuropathic pain and DNP [12, 24-30]. It has been postulated that limitations in these techniques' focality, penetration, and targeting control limit their therapeutic efficacy [31-35]. Electrosonic Stimulation (ESStim™) is an improved NIBS modality that overcomes the limitations of other technologies by combining independently controlled electromagnetic and ultrasonic fields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue [36]. This proposal is focused on evaluating whether our noninvasive ESStim system can effectively treat DNP. First in Phase I, to assess the feasibility of the proposed work, we will follow 20 DNP patients after giving a fixed dose of ESStim for 5 consecutive days, 20 min/day (10 SHAM ESStim, 10 ESStim™). We will administer a battery of safety, pain, quantitative sensory testing (QST), motor function, and global self-assessments (e.g., QOL), and actigraphy measures in the patients, evaluated over the treatment period and for at least six weeks following the last treatment session. Next in Phase II, we will follow 40 DNP patients (20 ESStim, 20 SHAM) after giving a fixed dose of stimulation for 5 consecutive days, 20 min/day, followed by three weeks of bi- weekly stimulation, 20 min/day (11 total stimulations). We will evaluate these patients with the same battery of assessments validated in Phase I, and compare the efficacy of the tested interventions for at least eight weeks following the last treatment session. In parallel with the DNP treatments, we will build MRI derived models of the stimulation fields in the heads (electric and acoustic field models) of the DNP patients to calculate the stimulation field characteristics at the brain target sites. Multivariate linear and generalized linear regression models will then be built and evaluated to predict the DNP patient outcomes related to pain, physical function, and psychosocial assessments as a function of baseline disease characteristics and the MRI based dosing models. The computational work will be combined to develop an optimized DNP ESStim dosing model. Overall, we hypothesize that the proposed experiments, computational studies, and technology development will allow us to optimize ESStim™ for treatment of central pain in DNP.