MR Imaging of the Excitatory and Inhibitory Neurotransmitters in Chronic Pain

慢性疼痛中兴奋性和抑制性神经递质的磁共振成像

• 批准号: 8243836
• 负责人: Bradley Foerster
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243836
• 关键词: Acute; Aminobutyric Acids; Anterior; Anti-Inflammatory Agents; Anti-inflammatory; Anticonvulsants; Biochemistry; Brain; Brain region; Characteristics; Chronic low back pain; Clinical; Clinical Management; Clinical assessments; Development; Diabetic Neuralgia; Discrimination; Evaluation; Excitatory Amino Acid Antagonists; Exhibits; Fatigue; Freedom; Functional disorder; Glutamates; Glutamine; Goals; Imaging Techniques; Individual; Insula of Reil; Intervention; Knee Osteoarthritis; Logistic Regressions; Logistics; Low Back Pain; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Mediating; Medical; Memory; Methodology; Methods; Mood Disorders; Neuraxis; Neurotransmitters; Norepinephrine; Operative Surgical Procedures; Opioid; Outcome; Pain; Pain Clinics; Pain-Free; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Physicians; Population; Process; Questionnaires; Recruitment Activity; Refractory; Regression Analysis; Reporting; Research Design; Role; Serotonin; Sleeplessness; Stratification; Subgroup; Symptoms; Syndrome; Techniques; Testing; Thalamic structure; Veterans; base; brain metabolism; central pain; chronic pain; cingulate cortex; clinical Diagnosis; cost; design; effective therapy; gamma-Aminobutyric Acid; improved; inhibitor/antagonist; insight; neuroimaging; novel; operation; research study; response; uptake

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.

描述（由申请人提供）： 具体目标：该提案的总体目标是开发一种可靠的策略，用于使用临床特征、实验性疼痛测试和磁共振波谱（MRS）区分以中枢疼痛为主的外周疼痛为主的膝关节骨关节炎（KOA）、慢性腰痛（CLBP）和疼痛性糖尿病神经病变（DPN）患者。我们将研究兴奋性（谷氨酸+谷氨酰胺（Glx）和N-乙酰谷氨酸（NAAG））以及抑制性（γ-氨基丁酸（GABA））神经递质使用建立和新的MRS技术。用于MRS的体素将被放置在涉及疼痛处理的大脑区域中，包括前扣带回、后扣带回、前扣带皮层和丘脑。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，提示CNS对其疼痛有显著影响（即显著中枢性疼痛 组件）。2.使用常规MRS技术，确定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，确定中枢性疼痛为主的慢性疼痛状态是否具有降低的GABA（一种主要的抑制性神经递质）水平和降低的NAAG（一种谷氨酸拮抗剂）水平。研究设计和方法：本研究将采用横断面设计，比较70例KOA受试者、70例CLBP受试者、30例DPN受试者和30例无疼痛对照。受试者将在4年内招募;患者受试者将来自安阿伯VA疼痛诊所。受试者将接受临床疼痛问卷调查、临床疼痛实验表征以及既定和新型（MEGA-PRESS）MR波谱技术，以评估中枢与外周疼痛优势。将使用逻辑判别法开发基于疼痛测量的逻辑回归分类器，以确定疼痛症状的外周与中枢优势。将使用横断面回归分析评估Glx和GABA与受试者组（中枢疼痛为主、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/分层措施控制潜在混杂因素，如疼痛和精神病药物。意义：慢性疼痛综合征在退伍军人群体中很常见，并且通常对现有的治疗和干预措施很难治疗。据估计，30-40%的疼痛综合征通常被认为是“中枢”介导的，具有重要的中枢成分;这是一个重要的区别，因为中枢和外周疼痛主要实体的治疗明显不同。对神经抑制（GABA）和神经兴奋（Glx & 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基于个体的治疗机会方面都具有很大的潜力。 公共卫生关系： 这项研究将确定慢性疼痛的临床和神经影像学标志物，以提供基于个体的治疗。本研究将慢性疼痛受试者（膝关节骨关节炎、腰痛和疼痛性糖尿病神经病变）分为两组：以中枢疼痛为主的症状组和以外周疼痛为主的症状组。这两组患者对药物治疗的反应是完全不同的，因此，正确分类慢性疼痛患者的可靠策略提供了提供有针对性的有效治疗的机会。慢性疼痛是VA退伍军人人群中的普遍问题，具有显著的相关成本;特别是膝关节骨关节炎、慢性腰痛和疼痛性糖尿病神经病变在该人群中很常见。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，以提高我们对慢性疼痛的理解，改善患者的预后。