Noninvasive brain stimulation for pain suppression

 描述（由申请人提供）：本提案包括Highland Instruments的商业机密和其他专有或机密信息，仅供美国国立卫生研究院（NIH）用于评估本SBIR提案。不授予其他权利。未经Highland Instrument许可，不得在NIH之外披露本建议书以及其中包含的商业秘密和其他专有或机密信息的全部或部分内容。此限制并不限制NIH使用数据中包含的信息的权利，如果它是从另一个来源不受限制地获得的。本图例适用于整个提案，包括但不限于本提案的摘要介绍、具体目标、研究计划（所有组成部分）、商业化计划和人类受试者部分。抽象的。膝关节OA是慢性疼痛和残疾的主要原因[1]。传统的治疗方法不能直接解决疼痛 感觉是在大脑中处理的[2-5]，并且机械关节功能障碍可因慢性疼痛引起的大脑运动控制中心的变化而恶化[6]。非侵入性脑刺激（NIBS）已成功应用于治疗某些疾病状态下的慢性疼痛，其中治疗诱导的脑活动变化恢复了与慢性疼痛感知/感觉相关的适应不良可塑性[3，5，7]。然而，最常见的NIBS方法（经颅磁刺激（TMS）和经颅直流电刺激（tDCS））未能显示出与传统疼痛治疗相同的一致临床获益，并且通常不用于OA治疗[8，9]。据推测，这些技术的局限性，渗透性和靶向控制限制了其治疗效果[10-14]。超声电刺激（ESStim（tm））是一种改进的NIBS模式，通过将独立控制的电磁场和超声场相结合，通过神经组织中的调谐机电耦合聚焦和增强刺激电流，克服了其他技术的局限性。该提案的重点是评估我们的无创ESStim系统是否可以有效治疗慢性OA疼痛，从而改善膝关节生物力学功能和患者生活质量（QOL）。首先在第一阶段评估拟议工作的可行性，我们将在连续5天给予恒定固定剂量的ESStim 20分钟/天后随访16名OA患者（8名假ESStim，8名ESStim）。我们将评估患者的安全性、疼痛、生物力学膝关节功能和QOL指标，在治疗期间和末次治疗后至少6周进行评价。接下来在第二阶段，我们将在两周内给予恒定固定剂量的刺激10天，20分钟/天后随访64名OA患者。患者将被随机分配至4种刺激条件之一：ESStim、tDCS、经颅超声（TUS）或假ESStim。我们将使用在I期研究中验证的疼痛、生物力学、QOL和安全性指标对这些患者进行评估，并在最后一次治疗后至少8周内比较受试干预措施的疗效。此外，我们将测试ESStim疼痛抑制是否可以由基线疾病状态指导。为了验证这一点，我们将建立和评估多变量线性和广义线性回归模型，以预测临床结果并确定最佳反应者。总体而言，我们假设所提出的实验、计算研究和技术开发将使我们能够测试ESStim在OA患者中的有效性。这项工作将作为未来大规模多中心研究的基础，并进一步推动ESStim OA治疗的商业化。

 DESCRIPTION (provided by applicant): This proposal includes trade secrets and other proprietary or confidential information of Highland Instruments and is being provided for use by the National Institutes of Health (NIH) for the sole purpose of evaluating this SBIR proposal. No other rights are conferred. This proposal and the trade secrets and other proprietary or confidential information contained herein shall further not be disclosed in whole or in parts, outside of NIH without Highland Instrument's permission. This restriction does not limit the NIH's right to use information contained in the data if it is obtained from another source without restriction. This legend applies to the entire proposal, including, but not limited to the Abstract Introduction, Specific Aims, Research Plan (all components), Commercialization Plan, and Human Subject's Sections of this proposal. Abstract. OA of the knee is a leading cause of chronic pain and disability [1]. Conventional treatments do not directly address the fact that pain sensation is processed in the brain [2-5] and mechanical joint dysfunction can be worsened by chronic pain induced changes in the brain's motor control centers [6]. 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 [3, 5, 7]. However the most common NIBS methods, Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), fail to show consistent clinical benefit on par with that of the conventional pain treatments and are not commonly used for OA therapy [8, 9]. It has been postulated that limitations in these techniques' focality, penetration, and targeting control limit their therapeutc efficacy [10-14]. Electrosonic Stimulation (ESStim(tm)) 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. This proposal is focused on evaluating whether our noninvasive ESStim system can effectively treat chronic OA pain, and in turn improve knee biomechanical function and patient quality of life (QOL). First in Phase I to assess the feasibilit of the proposed work, we will follow 16 OA patients after giving a constant fixed dose of ESStim for 20 min/day on 5 consecutive days (8 SHAM ESStim, 8 ESStim). We will assess a battery of safety, pain, biomechanical knee function, and QOL 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 64 OA patients after giving a constant fixed dose of stimulation for 10 days, 20 min/day, over a two-week period. Patients will randomly be assigned to 1 of 4 stimulation conditions: ESStim, tDCS, transcranial ultrasound (TUS), or SHAM ESStim. We will evaluate these patients with the battery of pain, biomechanical, QOL, and safety measures, which were validated in the Phase I studies, and compare the efficacy of the tested interventions for at least eight weeks following the last treatment session. Furthermore, we will test whether the ESStim pain suppression can be guided by the baseline disease state. To test this we will build and evaluate multivariate linear and generalized linear regression models to predict the clinical outcomes and identify best responders. Overall, we hypothesize that the proposed experiments, computational studies, and technology development will allow us to test the effectiveness of ESStim in OA patients. The work will serve as the basis for a future large-scale multicenter study and further the commercialization of ESStim OA therapy.