Multisite adaptive brain stimulation for multidimensional treatment of refractory chronic pain

多部位自适应脑刺激用于多维治疗难治性慢性疼痛

• 批准号: 9932780
• 负责人: Prasad Shirvalkar
• 金额: $ 151.28万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9932780
• 关键词: Absence of pain sensation; Accelerometer; Acute; Address; Adult; Affect; Affective; Algorithms; Amygdaloid structure; Analgesics; Anatomy; Anterior; Attention; Bilateral; Biological Markers; Brain; Brain region; Chronic; Clinical Trials; Cognitive; Computer software; Cross-Over Trials; Data; Deep Brain Stimulation; Detection; Development; Devices; Dimensions; Disease; Double-Blind Method; Electrodes; Failure; Feedback; Frequencies; Goals; Healthcare; Home environment; Implant; Individual; Inpatients; Insula of Reil; Intractable Pain; Location; Measures; Memory; Methods; Modeling; Moods; Motivation; Nervous system structure; Operative Surgical Procedures; Opioid; Outcome; Outcome Measure; Pain; Pain Disorder; Pain Measurement; Pathologic; Patient Selection; Patients; Pharmaceutical Preparations; Physiological; Physiology; Positioning Attribute; Prefrontal Cortex; Protocols documentation; Refractory; Reporting; Resistance; Sensory; Signal Transduction; Site; Subgroup; Syndrome; Technology; Testing; Thalamic structure; Therapeutic; Therapeutic Effect; Time; animal imaging; base; candidate marker; chronic pain; comparative efficacy; experience; human imaging; imaging study; implantable device; implantation; improved; multimodality; neurophysiology; neurotransmission; new technology; novel; novel therapeutics; pain processing; pain relief; pain score; pain signal; programs; relating to nervous system; response; somatosensory; symposium

PROJECT SUMMARY A diverse array of chronic pain syndromes are refractory to almost all treatment but involve pathological activity in similar brain regions. This suggests therapeutic potential for deep brain stimulation (DBS) for refractory pain disorders, but despite early promise, long-term efficacy is lacking. Current DBS devices are limited in anatomical reach, targeting only a subset of the distinct brain regions known to be important. Further, DBS therapy is bluntly applied in an “open-loop,” continuous fashion without regard to underlying physiology. As a result of these shortcomings, DBS for pain is often ineffective or shows diminished effect over time. Loss of therapeutic effect may be due to nervous system adaptation or a failure of stimulation to accommodate patient- specific dynamics of pain processing. DBS could be significantly improved by seeking individually optimized brain targets or by using neural biomarkers of pain to selectively control stimulation when it is needed (“closed-loop” DBS). Better brain targets would also address the different dimensions of pain such as somatosensory (location, intensity and duration), affective (mood and motivation) and cognitive (attention and memory). The main goal of this study is to test the feasibility of personalized targeting of brain regions that support multiple pain dimensions and to develop new technology for “closed-loop” DBS for pain. We will develop data-driven stimulation control algorithms to treat chronic pain using a novel device (Medtronic Summit RC+S) that allows longitudinal intracranial signal recording in an ambulatory setting. By building this technology in an implanted device, we will tailor chronic pain DBS to each patient and advance precision methods for DBS more generally. Beginning with an inpatient trial period, subjects with various refractory chronic pain syndromes will undergo bilateral surgical implant of temporary electrodes in the thalamus, anterior cingulate, prefrontal cortex, insula and amygdala. These regions have been implicated in the multiple dimensions of pain. The goal of the trial period is to identify candidate biomarkers of pain and optimal stimulation parameters for each individual, and to select subjects who show likelihood to benefit from the trial. A subgroup of 6 such patients will then proceed to chronic implantation of up to 3 “optimal” brain regions for long-term recording and stimulation. We will first validate biomarkers of low- and high-pain states to define neural signals for pain prediction in individuals (Aim 1). We will then use these pain biomarkers to develop personalized closed-loop algorithms for DBS and test the feasibility of performing closed-loop DBS for chronic pain in weekly blocks (Aim 2). We will then assess the efficacy of closed-loop DBS algorithms against traditional open-loop DBS or sham in a double-blinded cross- over trial (Aim 3) and measure mechanisms of DBS tolerance. Our main outcome measures will be a combination of pain, mood and functional scores together with quantitative sensory testing. Successful completion of this study would result in the first algorithms to predict real-time fluctuations in chronic pain states and development of a new therapy for currently untreatable diseases.

项目摘要 慢性疼痛综合症的潜水员阵列几乎对所有治疗都是难治性的，但涉及病理活性 在类似的大脑区域。这表明对难治性疼痛的深脑刺激（DBS）的热潜力 疾病，但迫切的早期承诺，缺乏长期效率。当前的DBS设备在解剖学上受到限制 到达，仅针对已知重要的大脑区域的一个子集很重要。此外，DBS治疗直率 以“开环”的持续方式应用，而无需考虑潜在的生理学。结果 缺点，疼痛的DBS通常无效或随着时间的流逝显示效果减少。丧失治疗作用 可能是由于神经系统的适应或刺激失败以适应患者特定动态 疼痛处理。通过寻求单独优化的大脑目标或通过 使用疼痛的神经生物标志物在需要时选择性控制刺激（“闭环” DBS）。更好的 大脑目标还将解决疼痛的不同维度，例如体感（位置，强度和 持续时间），情感（情绪和动机）和认知（注意力和记忆）。这项研究的主要目标是 测试支持多个疼痛维度的大脑区域的个性化靶向性的可行性 为“闭环” DB开发新技术，以供疼痛。我们将开发数据驱动的仿真控制 使用新型装置（Medtronic Summit RC+S）治疗慢性疼痛的算法，该算法允许纵向 在门诊环境中记录颅内信号。通过在植入设备中构建这项技术，我们将 为每个患者量身定制慢性疼痛DB，并更普遍地使用DBS的精确度。 从住院试验期开始，患有各种难治性慢性疼痛综合征的受试者将 在丘脑，前扣带回，前额叶皮层中进行临时电极的双侧手术植入物， 岛和杏仁核。这些区域已在疼痛的多个维度中暗示。目标的目标 试验期是确定每个人的疼痛和最佳刺激参数的候选生物标志物，以及 选择表现出可能从审判中受益的受试者。然后将有6个这样的患者组成的子组 长期记录和刺激的最多3个“最佳”大脑区域的慢性植入。我们将首先 验证低迷状态的生物标志物，以定义个体疼痛预测的神经元信号（AIM 1）。然后，我们将使用这些疼痛生物标志物来开发DBS的个性化闭环算法，并测试 在每周块中执行闭环DBS慢性疼痛的可行性（AIM 2）。然后，我们将评估 闭环DBS算法对传统开环DB的效率 超过试验（AIM 3）并测量DBS公差的机制。我们的主要结果措施将是一个组合 疼痛，情绪和功能分数以及定量感觉测试。成功完成 研究将导致第一种算法预测慢性疼痛状态和发育的实时波动 目前针对目前不可治疗的疾病的新疗法。