Post exertion malaise in GWI_Brain autonomic and behavioral interactions

GWI_Brain 自主神经和行为相互作用中的劳累后不适

• 批准号: 9210549
• 负责人: DANE B. COOK
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210549
• 关键词: Acute; Address; Afghanistan; Behavioral; Brain; Cardiac; Cardiovascular system; Caring; Cerebrovascular Circulation; Characteristics; Chronic; Chronic Fatigue Syndrome; Cognition; Country; Data; Evidence Based Medicine; Exercise; Exertion; Fatigue; Fibromyalgia; Financial compensation; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Glucocorticoid Receptor; Goals; Gulf War; Health; Heart Rate; Homeostasis; Hour; Immune; Immune system; Impaired cognition; Impairment; Inflammation Mediators; Inflammatory; Institute of Medicine (U.S.); Intervention; Iraq; Laboratories; Lasso; Leukocytes; Maintenance; Malaise; Measures; Medical; Metabolic; Methods; Mission; Modeling; Musculoskeletal Pain; Neuraxis; Pain; Paint; Pathway interactions; Patients; Persian Gulf; Physiological; Physiology; Positioning Attribute; Posture; Publishing; Regulation; Reporting; Research; Research Personnel; Rest; Stimulus; Study models; Symptoms; System; Testing; Time; Veterans; Viscera; War; Work; autonomic nerve; base; cerebrovascular; clinical care; cognitive function; cognitive task; cytokine; design; disability; experience; health care service utilization; immunoregulation; improved; individualized medicine; instrument; personalized medicine; public health relevance; relating to nervous system; response; stressor; targeted treatment; therapy design

 DESCRIPTION (provided by applicant): The overall goal of this research is to determine the mechanisms of symptom maintenance and exacerbation in Gulf War Veterans (GVs) suffering with Gulf War illness (GWI). To date, the pathophysiology of GWI is poorly understood, and there are currently no confirmed efficacious treatments for these Veterans. Research involving GVs and civilians with similar chronic multi-symptom illnesses (CMI) such as chronic fatigue syndrome and fibromyalgia show that multiple physiological systems are dysfunctional - principally the central, autonomic, and immune systems. Moreover, dysfunction within these systems is magnified and symptoms are exacerbated following an exercise challenge (i.e., post-exertion malaise [PEM]), providing a controllable model for the study of GWI. Our central hypothesis is that dysfunction across multiple physiological systems interacts to produce and maintain the symptoms of GWI, and this dysfunction is best studied via a PEM model. Our pilot data demonstrate that compared with healthy controls, patients with CMI (including GVs) demonstrate: (1) enhanced ratings and brain responses to painful stimuli and poor cerebral vascular auto-regulation, (2) augmented ratings and neural responses to fatiguing cognitive tasks, and (3) enhanced symptoms, increased pain sensitivity, and up-regulated gene expression to exercise challenge. These systems have been primarily studied in isolation and need to be studied under the same circumstances and within the same Veterans to determine the pathophysiological significance of their interactions. The primary goals of this project will b accomplished by comparing GVs with GWI to healthy GVs. The specific aims of the project are to determine: (1) baseline function across multiple physiological systems (CNS, autonomic, immune) in GVs with and without GWI; (2) the impact of an exercise challenge on CNS regulation of pain/fatigue, cardiovascular autonomic function, and immune system activity and symptoms in GVs with and without GWI; and (3) whether interactions among multiple systems significantly explain symptoms of GWI. CNS regulation of pain/fatigue will be measured using functional magnetic resonance imaging. Autonomic regulation will be measured via cerebral blood flow and parasympathetic responses to postural challenge. Immune activity will be measured via gene expression of inflammatory mediators (i.e., pro-inflammatory cytokine, metabolic and glucocorticoid receptors). The exercise challenge will consist of a single bout of cycling on a standard cycle ergometer at 70% of predicted peak heart rate for 30 minutes. CNS regulation of paint/fatigue, autonomic regulation, and immune activity will be measured 24 hours post-exercise when Veterans are experiencing PEM. Symptoms will be measured with validated instruments to assess pain, fatigue, and cognitive impairment. Symptoms will be followed for one week after exercise challenge to characterize the presence, magnitude, and time-course of PEM in GWI. We expect that GVs with GWI will demonstrate dysfunction across multiple physiological systems, that these systems will become more impaired as a result of an exercise challenge, and that interactions among these systems will significantly explain symptoms at baseline and during symptom exacerbation (i.e., PEM). The goals of this project will significantly enhance our understanding of GWI and will begin to determine the physiological systems that are most impaired. Study findings will provide the first critical steps towards designing treatments for GWI that are mechanistically based on physiology rather than standard approaches designed to target symptoms. These goals are consistent with a recent Institute of Medicine evidence-based review (IOM, 2014) of treatment options for Veterans of Gulf, Iraq,and Afghanistan citing the need for individualized treatments that are specific to the Veteran. This treatment approach cannot be realized without first determining the pathophysiology of GWI - the primary goal of the proposed research.

 描述（由申请人提供）： 本研究的总体目标是确定症状维持的机制， 海湾战争退伍军人（GV）患有海湾战争疾病（GWI）。到目前为止，GWI的病理生理学知之甚少，目前还没有确认的有效治疗这些退伍军人。对患有慢性疲劳综合征和纤维肌痛等类似慢性多症状疾病（CMI）的GV和平民的研究表明，多个生理系统功能失调-主要是中枢，自主神经和免疫系统。此外，这些系统内的功能障碍在运动挑战后被放大并且症状加剧（即，运动后不适[PEM]），为GWI的研究提供了一个可控的模型。 我们的中心假设是，多个生理系统的功能障碍相互作用， 产生并维持GWI的症状，这种功能障碍最好通过PEM模型进行研究。我们 试验数据表明，与健康对照相比，患有CMI（包括GV）的患者表现出：（1）对疼痛刺激的等级和脑反应增强，以及脑血管自动调节差，（2）对疲劳认知任务的等级和神经反应增强，以及（3）症状增强，疼痛敏感性增加，以及对运动挑战的基因表达上调。这些系统主要是孤立地研究的，需要在相同的情况下和相同的退伍军人中进行研究，以确定它们相互作用的病理生理学意义。本项目的主要目标将通过比较具有GWI的GV与健康GV来完成B。该项目的具体目标是确定：（1）多个生理系统的基线功能（2）运动挑战对具有和不具有GWI的GV中的疼痛/疲劳、心血管自主神经功能和免疫系统活性和症状的CNS调节的影响;（3）多系统间的相互作用是否能显著解释GWI的症状。将使用功能性磁共振成像测量疼痛/疲劳的CNS调节。自主神经调节将通过脑血流量和副交感神经对姿势挑战的反应来测量。免疫活性将通过炎症介质的基因表达来测量（即，促炎细胞因子、代谢和糖皮质激素受体）。运动挑战将包括在标准自行车测力计上以70%的预测峰值心率进行单次骑行30分钟。当退伍军人经历PEM时，将在运动后24小时测量油漆/疲劳、自主调节和免疫活性的CNS调节。将使用经验证的工具测量症状，以评估疼痛、疲劳和认知障碍。运动激发后将对症状进行为期一周的随访，以表征GWI中PEM的存在、程度和时程。我们预计，GWI的GV将表现出多个生理系统的功能障碍，这些系统将由于运动挑战而变得更加受损，并且这些系统之间的相互作用可能会导致运动障碍。 系统将显著地解释基线和症状恶化期间的症状（即，PEM）。 这个项目的目标将大大提高我们对GWI的理解，并将开始确定 受损最严重的生理系统。研究结果将提供第一个关键步骤 设计治疗GWI的方法，这些方法是基于生理学而不是 针对症状设计的标准方法。这些目标与最近医学研究所对海湾，伊拉克和阿富汗退伍军人治疗方案的循证审查（IOM，2014）一致，引用了退伍军人特定的个性化治疗的需求。如果不首先确定GWI的病理生理学，这种治疗方法就无法实现-这是拟议研究的主要目标。