Acute exercise tolerance among Veterans with Gulf War Illness

此职业发展奖(CDA-2)申请的目的是促进雅各布·林德海默博士 从慢性、多症状疾病(CMI)的新研究者过渡到独立的翻译人员 退伍军人管理局医疗系统的调查员。CDA-2的具体重点是研究有氧运动 一种被称为海湾战争病的流行的、使人衰弱的CMI不耐受。林德海默博士是一位综合性的 具有运动科学领域背景的心理生理学家，目前是博士后研究员 在退伍军人事务部新泽西州医疗系统的战争相关疾病和伤害研究中心。他的工作很密切 与他的共同导师戴恩·库克博士和迈克尔·法尔沃博士一起，进行了一项关于病理的多站点功绩回顾研究- GWI的生理机制。这一CDA-2将使林德海默博士在临床上获得更多技能 试验和生物统计学，(2)免疫分析数据的分析和解释，以及(3)临床锻炼 生理学测试。林德海默博士的另一个培训目标是继续开发神经成像 他在博士后奖学金培训期间获得的技能。神经成像不会被用作 拟议研究中的结果衡量，但将是后续功绩审查的重要组成部分 在本CDA-2的第五年申请。 研究计划的总体目标是为开发运动处方提供关键信息 这对于有GWI的退伍军人来说是可以容忍的。为此，开发了一种新颖和创新的研究设计 测量有氧运动强度和普遍现象之间的剂量-反应关系 影响CMI人群的疾病(如海湾战争疾病、肌肉痛脑脊髓炎/慢性疲劳综合征、 纤维肌痛)称为运动后不适(PEM)。尽管很明显，有氧运动可以诱导 PEM，运动的特定特征并不能引起PEM。受试者内部，随机的，受控的， 交叉研究将测试轻、中、剧烈运动对症状、行为和运动的影响 40例GWI退伍军人的PEM生物学指标 我们的中心假设是，运动与运动之间存在剂量依赖的关系 强度和PEM，表现为：GWI症状严重程度增加(目标1)，疼痛增加 敏感性(目标1)，认知能力下降(目标1)，促炎和 调节性细胞因子(即IL-6、IL-8、IL-10、肿瘤坏死因子-α)(目标2)、体力活动行为减少(目标3)以及 久坐行为的增加(目标3)。将使用经过验证的问卷来衡量GWI症状。 疼痛敏感度将通过心理-物理程序进行测量，以确定对 一系列热刺激。认知表现将通过计算机版本的PACE进行测量 听觉序列加法任务。促炎细胞因子将通过多细胞因子阵列使用 电化学发光平台。体力活动和久坐行为将通过 加速度计。参与者将完成最初的熟悉实验室访问，随后将完成另外四个 实验性的访问。目标1和目标2中的所有措施将在20分钟之前和之后立即实施 有氧自行车运动的一部分。目的3在每次试验性访问后采取为期一周的措施。 在一周的体力活动监测和一周的额外恢复(总共两周)之后， 参与者将返回实验室，完成随后的实验访问。 林德海默博士将利用这项研究的发现来开发一种基于证据的运动处方 预防GWI退伍军人PEM的症状、行为和生物学后果。使用数据 从这项研究中收集到的技能和经验以及从严格的职业发展计划中获得的技能和经验 林德海默博士和他的指导团队已经开发出，这种基于证据的练习的有效性 处方将在一项功绩审查调查中进行测试，调查重点是更广泛的CMIS退伍军人。

The purpose of this Career Development Award (CDA-2) application is to facilitate Dr. Jacob Lindheimer's transition from a new investigator of chronic, multi-symptom illnesses (CMI) into an independent translational investigator in the VA Healthcare System. The specific focus of this CDA-2 is on studying aerobic exercise intolerance in a prevalent and debilitating CMI known as Gulf War Illness. Dr. Lindheimer is an integrative psycho-physiologist with a background in the field of exercise science and is currently a Post-Doctoral Fellow at the War Related Illness and Injury Study Center of the VA New Jersey Healthcare System. He works closely with his co-mentors, Drs. Dane Cook and Michael Falvo, on a multi-site Merit Review study of patho- physiological mechanisms in GWI. This CDA-2 will allow Dr. Lindheimer to obtain additional skills in (1) clinical trials and biostatistics, (2) analysis and interpretation of immunological assay data, and (3) clinical exercise physiology testing. An additional training goal is for Dr. Lindheimer to continue developing the neuroimaging skills that he acquired during his post-doctoral fellowship training. Neuroimaging will not be used as an outcome measure in the proposed research, but will be an essential component of a subsequent Merit Review application in Year 5 of this CDA-2. The overall goal of the research plan is to provide critical information for developing an exercise prescription that is tolerable for Veterans with GWI. To that end, a novel and innovative study design has been developed to measure the dose-response relationship between aerobic exercise intensity and a pervasive phenomenon that affects CMI populations (e.g., Gulf War Illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Fibromyalgia) known as post-exertion malaise (PEM). Although it is clear that aerobic exercise can induce PEM, the specific features of exercise that elicit PEM are not. A within-subjects, randomized, controlled, crossover study will test the effect of light- moderate- and vigorous exercise on symptomatic, behavioral and biological indices of PEM in a sample of Veterans with GWI (n=40). Our central hypothesis is that is that there will be a dose-dependent, relationship between exercise intensity and PEM, which is manifested by: increases in GWI symptom severity (Aim 1), increases in pain sensitivity (Aim 1), decreases in cognitive performance (Aim 1), up-regulation of pro-inflammatory and regulatory cytokines (i.e., IL-6, IL-8, IL-10, TNF-α) (Aim 2), decreases in physical activity behavior (Aim 3), and increases in sedentary behavior (Aim 3). Validated questionnaires will be used to measure GWI symptoms. Pain sensitivity will be measured with psycho-physical procedures used to determine perceptual responses to a range of thermal stimuli. Cognitive performance will be measured with a computerized version of the Paced Auditory Serial Addition Task. Pro-inflammatory cytokines will be measured by multi-cytokine array using an electrochemiluminescence platform. Physical activity and sedentary behavior will be measured via accelerometry. Participants will complete an initial familiarization lab visit, followed by four additional experimental visits. All measures in Aims 1 and 2 will be administered immediately before and after 20 minutes of aerobic cycling exercise. Aim 3 measures will take place for one-week following each experimental visit. Following one week of physical activity monitoring and an additional week of recovery (two weeks total), participants will return to the lab to complete subsequent experimental visits. Dr. Lindheimer will use the findings from this study to develop an evidence based exercise prescription for preventing symptomatic, behavioral and biological consequences of PEM in Veterans with GWI. Using the data collected from this study and the skills and experiences obtained from the rigorous career development plan that Dr. Lindheimer and his mentoring team have developed, the efficacy of this evidence based exercise prescription will be tested in a Merit Review investigation focused on a broader range of Veterans with CMIs.