Brain Pathophysiology of Osteoarthritis Pain

摘要： 这是对PA-18-141和NIH HEAL倡议的修订提案，旨在解开 慢性骨关节炎（OA）膝关节疼痛的潜在机制。OA是最主要的肌肉骨骼慢性疼痛 然而，对慢性OA疼痛的机制知之甚少，这反映在目前的 药理学方法的效果最低，并且还没有开发出新的治疗方法。与此相反， 关节置换手术在大多数但不是所有OA患者中非常有效。由于不明原因，围绕 20%（仅在美国，2017年就有超过140，000例）的OA膝关节置换手术（TKR）未能缓解疼痛。我们 和其他人已经表明，在慢性OA疼痛的人中，大脑显示出适应不良的重组， 新皮质，皮质下边缘结构体积减少，OA疼痛的独特脑活动，以及全球 功能信息集成中断。这些结果共同暗示了人格、社会心理 认知、情感、感觉和运动功能（CESM能力）的状态和异常， 就我们所知，OA基本上还未被探索。此外，伤害性过程（外周和中枢 致敏、下行调节）被认为可能对OA的慢性化很重要。 因此，本提案的主要目标是（1）描述慢性膝关节骨性关节炎的神经机制 疼痛，和（2）定义区分TKR成功和失败的神经机制。我们建议可测试的 关于慢性OA疼痛的潜在机制和控制TKR结局的机制的假设。在目标1中， 我们将研究一大批接受TKR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），以表征脑回路（T1，DMRI，静息） 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、人格 和CESM能力。由于约80%的TKR在长期（12个月）内获得成功，我们假设， 在这些情况下，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，对心理社会属性的依赖性更强， 人格（基于边缘脑特性）。后一种假设将在短期内得到检验（3 目标2A中TKR后12个月）和长期（目标2B中TKR后12个月），通过构建模型 根据TKR前测量（在目标1中收集）预测TKR后短期和长期膝关节疼痛。在Aim中 3，将对TKR后3个月时疼痛缓解最大和最小的患者亚组进行全面重新评估， 认为相关的结局（目标1），随访，然后在TKR后12个月再次进行重新评估。结果 组与组之间以及组与组之间在时间上的对比将使我们能够识别膝关节手术的后果。 这些概述的研究扩展了我们目前关于慢性疼痛机制的一般知识， 更具体地用于OA和TKR后疼痛，潜在地揭示了新的治疗靶点。

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.