MR Imaging of the Excitatory and Inhibitory Neurotransmitters in Chronic Pain

描述(由申请人提供)： 具体目标：这项建议的首要目标是开发一种可靠的策略，利用临床特征、实验性疼痛测试和磁共振波谱(MRS)区分以中枢性疼痛为主的膝骨性关节炎(KOA)、慢性下腰痛(CLBP)和痛性糖尿病神经病变(DPN)患者。我们将使用已建立的和新的MRS技术来研究兴奋性(谷氨酸+谷氨酰胺(GLX)和N-乙酰天冬氨酸氨基(NAAG))和抑制性(伽马氨基丁酸(GABA))神经递质。MRS的体素将被放置在与疼痛处理有关的大脑区域，包括前岛、后岛、前扣带回皮质和丘脑。提出了以下具体目标：1.证明KOA、CLBP和DPN患者的不同亚组表现出症状特征和实验性疼痛测试参数，表明中枢神经系统对他们的疼痛(即显著的中枢性疼痛)有显著的贡献 组件)。2.使用传统的MRS技术，确定以中枢性疼痛为主的慢性疼痛状态是否具有升高的GLX水平，GLX是中枢神经系统中的主要兴奋成分。3.使用新的MRS技术，确定中枢疼痛主导的慢性疼痛状态是否降低了主要抑制性神经递质GABA的水平，以及谷氨酸的拮抗剂NAAG的水平。研究设计与方法：本研究采用横断面设计，对70名膝关节骨性关节炎患者、70名CLBP患者、30名DPN患者和30名无痛对照组进行比较。受试者将在四年内招募；患者受试者将来自Ann Arbor VA疼痛诊所。受试者将接受临床疼痛问卷、临床疼痛实验表征和已建立的和新的(巨型媒体)磁共振波谱技术，以评估中枢和外周疼痛的优势。将开发一种基于疼痛测量的Logistic回归分类器，使用Logistic判别来确定疼痛症状的外周优势与中枢优势。将使用横断面回归分析来评估GLX和GABA与受试者组(以中枢性疼痛为主、以外周疼痛为主、健康对照)和其他解释变量的相关性。将使用Logistic回归调整/分层措施来控制潜在的混杂因素，如疼痛和精神药物。意义：慢性疼痛综合征在退伍军人中很常见，而且对现有的治疗和干预措施往往难以奏效。据估计，通常被认为是“中枢”调节的疼痛综合征中，有30-40%具有重要的中枢成分；这是一个重要的区别，因为对中枢性和外周性疼痛的主要治疗实体明显不同。对神经抑制(GABA)和神经兴奋(GLX和NAAG)通路的评估在提高我们对慢性疼痛机制的理解以及有效的个体化治疗机会方面都提供了很有希望的潜力。 公共卫生相关性： 这项研究将确定慢性疼痛的临床和神经成像标记物，以努力提供基于个人的治疗。这项研究将慢性疼痛受试者(膝骨性关节炎、腰背痛和痛性糖尿病神经病变)分为两组：以中枢性疼痛症状为主的患者和以外周疼痛症状为主的患者。这两组人对医疗的反应截然不同，因此正确地对慢性疼痛患者进行分类的可靠策略为提供有针对性的有效治疗提供了机会。慢性疼痛是退伍军人群体中普遍存在的问题，相关费用巨大；尤其是膝骨性关节炎、慢性下腰痛和痛性糖尿病神经病变在这一人群中很常见。这项拟议的研究将使用不同的临床疼痛测试和先进的神经成像技术来提高我们对慢性疼痛的理解，并改善患者的预后。

DESCRIPTION (provided by applicant): Specific Aims: The overarching goal of this proposal is the development of a reliable strategy for differentiation of central pain predominant from peripheral pain predominant knee osteoarthritis (KOA), chronic low back pain (CLBP) and painful diabetic neuropathy (DPN) patients using clinical features, experimental pain testing and magnetic resonance spectroscopy (MRS). We will study both excitatory (glutamate + glutamine (Glx) and N-acetylasparatylglutamate (NAAG)) as well as inhibitory (gamma-Aminobutyric Acid (GABA)) neurotransmitters using established and novel MRS techniques. Voxels for MRS will be placed in brain regions implicated in pain processing including the anterior insula, posterior insula, anterior cingulate cortex, and thalamus. The following specific aims are proposed: 1. Demonstrate that distinct subgroups of KOA, CLBP and DPN patients exhibit a symptom profile and experimental pain testing parameters suggestive of significant CNS contribution to their pain (i.e. significant central pain component). 2. Using conventional MRS techniques, determine if central pain predominant chronic pain states have elevated levels of Glx, a major excitatory component in the central nervous system. 3. Using novel MRS techniques, determine if central pain predominant chronic pain states have reduced levels of GABA which is a major inhibitory neurotransmitter and lower levels of NAAG, an antagonist to glutamate. Study Design & Methods: The study will use a cross sectional design comparing 70 subjects with KOA, 70 subjects with CLBP, 30 subjects with DPN and 30 pain free controls. Subjects will be recruited over a four year period; patient subjects will come from the Ann Arbor VA Pain Clinic. Subjects will undergo clinical pain questionnaires, clinical pain experiment characterization and established and novel (MEGA-PRESS) MR spectroscopy techniques to assess for central versus peripheral pain predominance. A logistic regression classifier based on pain measures will be developed using logistic discrimination to determine peripheral versus central predominance of pain symptoms. A cross-sectional regression analysis will be used to assess the association of Glx and GABA with subject group (central pain predominant, peripheral pain predominant, healthy controls) and other explanatory variables. Potential confounders such as pain and psychiatric medications will be controlled for using logistic regression adjustments/stratification measures. Significance: Chronic pain syndromes are common in the Veteran population and are often refractory to available treatments and interventions. It is estimated that 30-40% of pain syndromes thought generally to be "centrally" mediated have an important central component; this is an important distinction as treatment for central and peripheral pain predominant entities are distinctictly different. Evaluation of both the neuroinhibitory (GABA) and neuroexcitatory (Glx & NAAG) pathways provides promising potential both in terms of improving our understanding of the mechanisms of chronic pain as well as opportunities for effective, individual-based treatments. PUBLIC HEALTH RELEVANCE: This study will identify clinical and neuroimaging markers in chronic pain in an effort to provide individual-based treatments. This study will differentiate chronic pain subjects (knee osteoarthritis, low back pain and painful diabetic neuropathy) into two groups: those who have central pain predominant symptoms and those who have peripheral pain predominant symptoms. The response to medical treatment between these two groups is quite different, thus a reliable strategy to correctly categorize chronic pain sufferers offers the opportunity to provid targeted, effective treatments. Chronic pain is a prevalent problem in the VA veteran population with significant associated costs; in particular knee osteoarthritis, chronic low back pain and painful diabetic neuropathy are common in this population. The proposed study will use different clinical pain tests and advanced neuroimaging techniques to improve our understanding of chronic pain and improve patient outcomes.