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: 10683715
• 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 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683715
• 关键词: Acute; Address; Afghanistan; Behavioral; Brain; Cardiac; Cardiovascular system; Caring; Central Nervous System; Cerebrovascular Circulation; Characteristics; Chronic; Chronic Fatigue Syndrome; Cognition; Compensation; Country; Data; Evidence Based Medicine; Exercise; Exertion; Fatigue; Fibromyalgia; Functional Magnetic Resonance Imaging; Functional disorder; Gene Expression; Glucocorticoid Receptor; Goals; Gulf War veteran; 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; Pain; Pain Measurement; Paint; Pathway interactions; Patients; Persian Gulf; Persian Gulf Syndrome; Physiological; Physiology; Positioning Attribute; Posture; Publishing; Regulation; Reporting; Research; Research Personnel; Rest; Stimulus; Study models; Symptoms; System; Testing; Time; Titrations; United States Department of Veterans Affairs; Veterans; Viscera; War; Work; autonomic nerve; cerebrovascular; clinical care; cognitive function; cognitive task; cytokine; design; disability; efficacious treatment; experience; health care service utilization; immunoregulation; improved; individualized medicine; instrument; neural; pain sensitivity; personalized medicine; public health relevance; 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）： 这项研究的总体目标是确定症状维持的机制和 海湾退伍军人（GVS）患有海湾战争疾病（GWI）的加剧。迄今为止，GWI的病理生理学知之甚少，目前尚无对这些退伍军人的有效治疗。涉及GVS和平民患有类似慢性多症状疾病（CMI）的研究，例如慢性疲劳综合征和纤维肌痛，表明多种物理系统功能障碍 - 主要是中心，自主和免疫系统。此外，这些系统内的功能障碍会被放大，并且在运动挑战（即，锻炼后不适[PEM]）后，符号会加剧，为GWI研究提供了受控的模型。 我们的核心假设是，跨多个物理系统的功能障碍与 生产和保持GWI的症状，并且最好通过PEM模型研究这种功能障碍。我们的 飞行员数据表明​​，与健康对照相比，CMI（包括GVS）的患者证明：（1）增强评分和大脑对疼痛刺激的反应和脑血管自动调节不良，（2）增强评分和对疲劳认知任务的神经反应增强，以及（3）增强症状的症状，增强疼痛的攻击，并增加疼痛敏感性，对痛苦敏感性，恢复性地恢复症状。这些系统主要是孤立研究的，需要在相同的情况下和在同一退伍军人中进行研究，以确定其相互作用的病理生理意义。该项目的主要目标将通过将GV与GWI与健康GV进行比较来实现。该项目的具体目的是确定：（1）具有和没有GWI的GVS中多个物理系统（CNS，自主，免疫）之间的基线功能； （2）运动挑战对CNS疼痛/疲劳，心血管自主功能以及具有GWI和没有GWI的GV的症状的影响； （3）多个系统之间的相互作用是否显着解释了GWI的症状。 CNS调节疼痛/疲劳将使用功能磁共振成像测量。将通过脑血流和对姿势挑战的副交感神经反应来衡量自主法规。免疫活性将通过炎症介质（即促炎性细胞因子，代谢和糖皮质激素受体）的基因表达来测量。运动挑战将包括在标准循环测力计上以预测峰值心率的70％进行30分钟的单一骑自行车组成。当退伍军人经历PEM时，运动后24小时将测量涂料/疲劳，自主性调节和免疫学活动的中枢神经系统调节。症状将使用经过验证的工具来评估疼痛，​​疲劳和认知障碍。运动挑战后，将遵循症状，以表征PEM在GWI中的存在，大小和时间阶段。我们预计，使用GWI的GVS会在多个物理系统中证明功能障碍，这些系统将由于运动挑战而受到损害，并且这些系统之间的相互作用将受到影响 系统将在基线和症状加剧期间显着解释症状（即PEM）。 该项目的目标将大大增强我们对GWI的理解，并将开始确定 最受损的物理系统。研究结果将提供第一个关键步骤 旨在设计基于生理学的GWI治疗方法，而不是 旨在针对症状的标准方法。这些目标与最近的医学循证研究所（IOM，2014年）一致，该研究对海湾，伊拉克和阿富汗的退伍军人的治疗方案是一致的，理由是需要对退伍军人特定的个性化治疗。如果不先确定GWI的病理生理学，这是拟议研究的主要目标，就无法实现这种治疗方法。