Vagal nerve stimulation to probe inflammation and brain in posttraumatic stress

迷走神经刺激可探测创伤后应激状态下的炎症和大脑

• 批准号: 10400008
• 负责人: Imanuel Ruvin Lerman
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400008
• 关键词: Afghanistan; Aftercare; Amygdaloid structure; Anxiety; Autonomic nervous system; Aversive Stimulus; Biological Markers; Brain; Brain imaging; Brain region; Chronic; Clinical Practice Guideline; DSM-V; Data; Development; Devices; Diagnosis; Effectiveness; FDA approved; Functional Magnetic Resonance Imaging; Functional disorder; Generations; Goals; Health; Heart Diseases; Immune System Diseases; Inflammation; Inflammatory; Insula of Reil; Interleukin-1 beta; Interleukin-6; Intervention; Intervention Studies; Iraq; K-Series Research Career Programs; Knowledge; Longevity; Measures; Mental disorders; Methods; Mission; Nerve; Neuraxis; Outcome; Pain; Participant; Pathogenesis; Pathologic; Perception; Peripheral; Pharmacologic Substance; Physiological; Physiology; Post-Traumatic Stress Disorders; Procedures; Psychotherapy; Quality of life; Reporting; Research; Research Training; Risk Factors; Scientist; Services; Severities; Signal Transduction; Stimulus; Symptoms; TNF gene; Technology; Time; Treatment Efficacy; Veterans; Vietnam; War; Work; World Health Organization Disability Assessment Schedule; active duty; base; chronic pain; combat; combat veteran; comorbidity; cytokine; daily functioning; effective therapy; follow-up; functional disability; functional outcomes; hypothalamic-pituitary-adrenal axis; immune activation; improved; improved functioning; indexing; mortality; neural circuit; neural correlate; neurobiological mechanism; neuroimaging; neuromechanism; neuropsychiatric disorder; neuroregulation; nociceptive response; novel strategies; pain processing; peripheral blood; physical symptom; post-traumatic stress; relating to nervous system; response; service member; symptomatic improvement; tool; vagus nerve stimulation

Abstract: Rates of posttraumatic stress disorder (PTSD) are high among combat Veterans with estimates of PTSD within Iraq and Afghanistan veterans at nearly 17% of active duty and over 24% of reserve service members that screen positive for PTSD. Studies from the current and prior wars have demonstrated that mental disorders, in particular PTSD, are associated with higher rates of: 1) physical symptoms, 2) chronic physical illness and 3) overall mortality. Rates of comorbid PTSD and chronic pain are exceedingly high among veterans with reports of 30%- 50% in both Vietnam and OEF/OIF Veterans, that suggest a shared pathophysiology. Excessive release of peripheral pro-inflammatory cytokines has been implicated in the generation of: 1) pathologic chronic pain states and 2) in PTSD. Perception of an aversive stimulus/threat activates peripheral inflammatory cytokine release, while exogenous administration of an inflammatory stimulus (that also cause release of peripheral inflammatory cytokines) increases the limbic (insular cortex and amygdala) response to aversive/threat stimuli as measured by functional Magnetic Resonance Imaging (fMRI). Work by our group [Lerman et al., (2016)(15)], shows that PTSD influences the: 1) nociceptive response, 2) intrathecal cytokine release and 3) peripheral cytokine release in response to a painful stimulus when compared to responses of Veteran combat controls (CC). Vagus nerve stimulation has been shown to decrease: 1) peripheral inflammatory cytokine release, 2) pain, and 3) anxiety. Recent work by our group has shown that non-invasive vagal nerve stimulation (nVNS; using extradermal stimulation) decreases peripheral inflammation in healthy control subjects and may similarly decrease hyperinflammation observed in PTSD [Lerman et al., (2016)(22)]. In pilot work, we have obtained initial fMRI evidence (preliminary data) suggests that in healthy controls, nVNS decreases insular response to painful stimuli, which is known to be dysregulated in PTSD. We plan to use nVNS as a probe in PTSD and CC to observe the effects of vagal nerve modulation on: 1) CNS neural circuit function during pain and pain anticipation stimuli, and 2) peripheral inflammatory biomarker measures. The long-term goal of this line of research is to use nVNS as a probe to obtain pilot data of: 1) peripheral inflammatory biomarkers and 2) fMRI derived brain imaging response to pain, to advance our understanding of fundamental pathophysiology of co-morbid pain and PTSD and to ultimately provide, targeted neuromodulation based interventions for veterans with pain and PTSD. We will study two groups [(PTSD, CC), (both without chronic pain diagnosis)], under two conditions (either nVNS or Sham stimulation), over three time points (pre-nVNS/Sham), (7 days post-nVNS/Sham) and one month after treatment (one month post- nVNS/Sham). The first objective of this proposal, is to measure peripheral inflammation in response to nVNS treatment in order to delineate peripheral inflammation based biomarker profiles of treatment responsiveness to nVNS in PTSD and CC. The second step is to measure brain region response to a pain and pain anticipation stimuli task before and after nVNS treatment in order to demonstrate: 1) a neural profile of treatment responsiveness to nVNS and 2) the neural profile of nVNS effects on pain in PTSD and CC. Participants will receive a 7-day long nVNS/Sham trial where inflammatory biomarkers, neuroimaging tools, PTSD symptom severity and functional life quality will be assessed before and after the 7 days. Additionally, PTSD symptom severity and functional life quality will be assessed one month after study onset. The direct contrast of pre and post nVNS/Sham will provide an objective and sensitive assessment of neuromodulation with nVNS and lay the groundwork for further neuromodulation based study in PTSD. Such outcomes may provide additional evidence of potential treatment efficacy, thus ultimately provide therapies that enhance VA clinical practice guidelines.

摘要： 创伤后应激障碍（PTSD）的发病率在退伍军人中很高， 伊拉克和阿富汗退伍军人占现役军人的近17%，超过24%的预备役军人接受筛查。 创伤后应激障碍呈阳性对当前和之前战争的研究表明，精神障碍，特别是 创伤后应激障碍，与较高的比率：1）身体症状，2）慢性身体疾病和3）整体 mortality.在退伍军人中，PTSD和慢性疼痛的共病率非常高，据报道有30%- 50%在越南和OEF/OIF退伍军人，这表明一个共同的病理生理学。过度释放 外周促炎细胞因子与以下的产生有关：1）病理性慢性疼痛状态 （2）PTSD。厌恶刺激/威胁的感知激活外周炎性细胞因子释放， 而外源性给予炎性刺激物（其也引起外周炎性 细胞因子）增加边缘系统（岛叶皮层和杏仁核）对厌恶/威胁刺激的反应， 功能性磁共振成像（fMRI）。我们小组的工作[Lerman等人，（2016）（15）]，显示， PTSD影响：1）伤害性反应，2）鞘内细胞因子释放和3）外周细胞因子释放 与退伍军人战斗控制（CC）的反应相比，迷走神经 刺激已显示减少：1）外周炎性细胞因子释放，2）疼痛，和3）焦虑。 我们小组最近的工作表明，非侵入性迷走神经刺激（nVNS;使用皮外 刺激）降低健康对照受试者的外周炎症，并且可以类似地降低 在PTSD中观察到的炎症过度[Lerman等人，（2016）（22）]。在试点工作中，我们已经获得了初步的功能磁共振成像， 证据（初步数据）表明，在健康对照中，nVNS降低了对疼痛刺激的岛叶反应， 已知在创伤后应激障碍中会失调 本研究拟以nVNS作为PTSD和CC的一种检测手段，观察迷走神经调节对以下方面的影响：1）中枢神经系统 疼痛和疼痛预期刺激期间的神经回路功能，和2）外周炎症生物标志物 措施这项研究的长期目标是使用nVNS作为探针，以获得以下试验数据：1） 外周炎症生物标志物和2）fMRI衍生的疼痛脑成像反应，以推进我们的研究。 了解共病疼痛和PTSD的基本病理生理学，并最终提供，有针对性的 神经调节为基础的干预与疼痛和创伤后应激障碍的退伍军人。我们将研究两组[（PTSD，CC）， (both无慢性疼痛诊断）]，在两种条件下（nVNS或假刺激），三次以上 点（nVNS/Sham前）、（nVNS/Sham后7天）和治疗后1个月（nVNS/Sham后1个月） nVNS/假手术）。该建议的第一个目标是测量nVNS引起的外周炎症反应 为了描绘基于外周炎症的治疗响应性的生物标志物谱， PTSD和CC中的nVNS。第二步是测量大脑区域对疼痛和疼痛预期的反应 在nVNS治疗之前和之后的刺激任务，以证明：1）治疗的神经概况 对nVNS的反应性和2）nVNS对PTSD和CC疼痛影响的神经特征。参与者将 接受为期7天的nVNS/Sham试验，其中炎症生物标志物、神经成像工具、PTSD症状 将在7天前后评估严重程度和功能性生活质量。此外，PTSD症状 在研究开始后一个月评估严重程度和功能性生活质量。前的直接对比和 术后nVNS/假手术将提供nVNS神经调节的客观和敏感的评估， 为进一步研究创伤后应激障碍的神经调节奠定基础。这样的结果可能会提供额外的证据 潜在的治疗效果，从而最终提供增强VA临床实践指南的疗法。