Brain Pathophysiology of Osteoarthritis Pain

骨关节炎疼痛的脑病理生理学

• 批准号: 10320397
• 负责人: Apkar Vania Apkarian
• 金额: $ 68.45万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320397
• 关键词: Age; Behavioral; Brain; Characteristics; Chronic; Clinical; Cognition; Cognitive; Data; Degenerative polyarthritis; Dependence; Emotional; Emotions; Esthesia; Excision; Failure; Female; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Goals; Healthcare; Helping to End Addiction Long-term; Hippocampus (Brain); Individual; Intervention; Joints; Knee; Knee Osteoarthritis; Knowledge; Link; Maintenance; Maps; Measures; Modeling; Moods; Motor; Neocortex; Neurologic; Nociception; Nociceptors; Operative Surgical Procedures; Outcome; Pain; Pain intensity; Pain management; Participant; Patient Schedules; Patients; Peripheral; Personality; Personality Assessment; Persons; Pharmaceutical Preparations; Pharmacology; Population; Process; Property; Psychophysics; Psychosocial Factor; Questionnaires; Replacement Arthroplasty; Rest; Role; Sensory; Spinal Cord; Structure; Subgroup; Technology; Testing; Time; United States National Institutes of Health; Validation; base; brain circuitry; central pain; central sensitization; chronic musculoskeletal pain; chronic pain; chronic pain relief; chronic painful condition; cohort; cost; design; knee pain; knee replacement arthroplasty; longitudinal design; male; multimodal neuroimaging; new therapeutic target; novel therapeutics; opioid epidemic; opioid use; osteoarthritis pain; pain patient; pain relief; patient subsets; predictive modeling; psychosocial; response; sex; study characteristics; success; surgery outcome; surgical pain; tool

Abstract: This is a revised proposal in response to PA-18-141 and the NIH HEAL initiative, designed to unravel mechanisms that underlie chronic osteoarthritis (OA) knee pain. OA is the leading musculoskeletal chronic pain condition worldwide, yet little is known about the mechanisms of chronic OA pain, reflected in the fact that current pharmacologic approaches are minimally effective and new treatments have not been developed. In contrast, joint replacement surgery is highly effective in most, but not all, patients with OA. For unknown reasons, around 20% (>140,000 cases in 2017 in the US alone) of OA knee replacement surgeries (TKR) fail to relieve pain. We and others have shown that in people with chronic OA pain, the brain shows maladaptive reorganization of the neocortex, diminished volumes of sub-cortical limbic structures, distinct brain activity for OA pain, and global disruption of functional information integration. Together these results imply altered personality, psychosocial status, and abnormalities in abilities for cognition, emotion, sensation and motor function (CESM-abilities), which to our knowledge remain essentially unexplored in OA. In addition, nociceptive processes (peripheral and central sensitization, descending modulation) have been considered as possibly being important for chronicity of OA. Hence, the primary goals of this proposal are (1) to characterize the neurologic mechanisms for chronic OA knee pain, and (2) to define neurologic mechanisms that differentiate success and failure of TKR. We propose testable hypotheses regarding mechanisms underlying chronic OA pain and those that control TKR outcomes. In Aim 1, we will study a large group of OA pain patients prior to TKR, as well as OA pain patients not undergoing TKR (positive control) and healthy individuals (negative control), to characterize brain circuitries (T1, DMRI, resting state fMRI) and determine how these map to nociception, to pain and related psychosocial status, personality, and CESM-abilities. Since ~80% of TKR are successful in the long term (12 months), we hypothesize that in these cases, the dominant parameter controlling pain is the OA joint-related nociceptive processes; while in cases where TKR fails in the long term, there is a stronger dependence on psychosocial attributes and personality (based on limbic brain properties). The latter hypothesis will be tested both over the short term (3 months post-TKR in Aim 2A) and in the long term (12 months post-TKR in Aim 2B), by constructing models from pre-TKR measures (collected in aim 1) to predict knee pain in the short and long term after TKR. In Aim 3, subgroups of patients with the greatest and least pain relief at 3 months post-TKR will be fully reassessed for outcomes deemed relevant (in Aim 1), followed, and then reassessed again at 12 months post-TKR. Outcome contrasts between groups, and within groups in time, will allow us to identify consequences of knee surgery. These outlined studies expand on our current knowledge regarding mechanisms of chronic pain in general, and more specifically for OA and for post-TKR pain, potentially unraveling novel therapeutic targets.

摘要： 这是一项针对PA-18-141和NIH Hear倡议的修订提案，旨在 慢性骨关节炎(OA)膝关节疼痛的机制。骨性关节炎是主要的肌肉骨骼慢性疼痛 世界范围内的情况，但对慢性骨性关节炎疼痛的机制知之甚少，反映在目前 药物治疗的效果微乎其微，而且还没有开发出新的治疗方法。相比之下， 关节置换手术对大多数但不是所有的骨性关节炎患者都非常有效。由于未知的原因，周围 20%的骨关节炎膝关节置换手术(TKR)无法缓解疼痛(仅在美国就有14万例)。我们 其他研究表明，在患有慢性骨性关节炎疼痛的人中，大脑表现出不适应的重组 新皮质，皮质下边缘结构体积减小，OA疼痛的明显脑活动，以及 功能信息整合中断。总而言之，这些结果意味着人格、心理社会的改变 认知、情感、感觉和运动功能的能力异常(CESM能力) 据我们所知，在办公自动化领域基本上仍未被探索。此外，伤害性突起(外周和中枢) 敏化、下行调制)被认为可能是骨性关节炎慢性化的重要因素。 因此，这项建议的主要目的是(1)描述慢性膝骨关节炎的神经学机制 疼痛，以及(2)定义区分TKR成功和失败的神经机制。我们提出了可测试性 关于慢性骨性关节炎疼痛的潜在机制和控制TKR结果的假说。在目标1中， 我们将研究一大组接受TKR前的骨性关节炎疼痛患者，以及未接受TKR的骨性关节炎疼痛患者 (阳性对照)和健康人(阴性对照)，以表征大脑回路(T1、DMRI、静息 状态fMRI)，并确定它们如何映射到伤害、疼痛和相关的心理社会状态、个性、 和CESM能力。由于约80%的TKR在长期(12个月)内成功，我们假设在 在这些病例中，控制疼痛的主要参数是OA关节相关的伤害性过程；而在 在TKR长期失败的情况下，对心理社会属性和 个性(基于边缘大脑的属性)。后一种假设将在短期内得到检验(3 目标2A中的TKR后12个月)和长期(目标2B中的TKR后12个月)，通过构建模型 根据TKR前的测量(在AIM 1中收集)来预测TKR后短期和长期的膝关节疼痛。在AIM 3、TKR术后3个月疼痛缓解程度最大和最小的患者亚组将完全重新评估 结果被认为是相关的(目标1)，跟踪，然后在TKR后12个月再次重新评估。结果 不同组之间和组内的对比将使我们能够及时确定膝盖手术的后果。 这些概述的研究扩展了我们目前关于慢性疼痛机制的一般知识，以及 更具体地说，针对骨关节炎和TKR后疼痛，潜在地解开了新的治疗靶点。