Brain Pathophysiology of Osteoarthritis Pain

骨关节炎疼痛的脑病理生理学

基本信息

批准号：
10165914
负责人：
Apkar Vania Apkarian
金额：
$ 15万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165914
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 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 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 multimodality 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

项目摘要

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.

抽象的：这是针对 PA-18-141 和 NIH HEAL 倡议的修订提案，旨在解决慢性骨关节炎（OA）膝关节疼痛的机制。 OA 是主要的肌肉骨骼慢性疼痛但对于慢性 OA 疼痛的机制却知之甚少，这反映在当前的事实中：药物方法的效果甚微，并且尚未开发出新的治疗方法。相比之下，关节置换手术对大多数（但不是全部）骨关节炎患者非常有效。不知什么原因，周围 20%（仅在美国 2017 年就有超过 140,000 例）骨关节炎膝关节置换手术 (TKR) 无法缓解疼痛。我们等人表明，患有慢性骨关节炎疼痛的人，大脑表现出适应不良的重组新皮质、皮质下边缘结构体积减少、OA 疼痛的独特大脑活动以及整体功能性信息整合的破坏。这些结果共同意味着人格、心理社会的改变认知、情感、感觉和运动功能（CESM-能力）的状态和异常，据我们所知，OA 领域基本上尚未被探索。此外，伤害感受过程（外周和中枢）敏化、下降调制）被认为可能对 OA 的慢性化很重要。因此，该提案的主要目标是（1）描述慢性膝关节骨关节炎的神经机制 (2) 定义区分 TKR 成功和失败的神经机制。我们建议可测试关于慢性 OA 疼痛的机制和控制 TKR 结果的假设。在目标 1 中，我们将研究大量进行 TKR 之前的 OA 疼痛患者，以及未接受 TKR 的 OA 疼痛患者（阳性对照）和健康个体（阴性对照），以表征大脑回路（T1、DMRI、静息状态）状态 fMRI）并确定这些如何映射到伤害感受、疼痛和相关的心理社会状态、性格、和CESM能力。由于约 80% 的 TKR 从长期（12 个月）来看是成功的，因此我们假设在这些病例中，控制疼痛的主要参数是 OA 关节相关的伤害性过程；当在在 TKR 长期失败的情况下，对心理社会属性的依赖性更强，并且个性（基于边缘脑特性）。后一个假设将在短期内得到检验（3 目标 2A 中的 TKR 后几个月）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（在目标 1 中收集）来预测 TKR 后短期和长期的膝关节疼痛。瞄准 3、TKR 后 3 个月时疼痛缓解程度最大和最小的患者亚组将被全面重新评估被认为相关的结果（在目标 1 中），随后进行跟踪，然后在 TKR 后 12 个月再次重新评估。结果组之间以及组内时间的对比将使我们能够确定膝关节手术的后果。这些概述的研究扩展了我们目前关于慢性疼痛机制的知识，并且更具体地说，针对 OA 和 TKR 后疼痛，可能会揭示新的治疗靶点。