Vagal nerve stimulation to probe inflammation and brain in posttraumatic stress

摘要： 创伤后应激障碍(PTSD)在退伍军人中的发病率很高，据估计 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 创伤后应激障碍阳性。来自当前和以前战争的研究表明，精神障碍，特别是 创伤后应激障碍与更高的发病率有关：1)身体症状，2)慢性身体疾病和3)总体 死亡率。退伍军人中患有创伤后应激障碍和慢性疼痛的比例非常高，报告称有30%- 在越南和OEF/OIF退伍军人中都有50%，这表明有共同的病理生理学。过量释放 外周促炎细胞因子参与了：1)病理性慢性疼痛状态的发生 2)创伤后应激障碍。对令人厌恶的刺激/威胁的感知激活了外周炎症细胞因子的释放， 同时外源性给予炎症刺激(这也会导致外周炎症的释放 细胞因子)增加边缘(岛叶皮质和杏仁核)对厌恶/威胁刺激的反应 通过功能磁共振成像(FMRI)。我们小组的工作[Lerman等人，(2016)(15)]表明 创伤后应激障碍影响：1)伤害性反应；2)鞘内细胞因子释放；3)外周细胞因子释放 与老兵战斗控制组(CC)的反应相比，对痛苦刺激的反应。迷走神经 刺激已被证明减少：1)外周炎性细胞因子的释放，2)疼痛，3)焦虑。 我们团队最近的工作表明，使用真皮外无创迷走神经刺激(nVNS； 刺激)可减少健康对照组受试者的外周炎症，并可类似地减少 在创伤后应激障碍中观察到过度炎症[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，在健康对照组中，nVNS降低了岛叶对疼痛刺激的反应， 它在创伤后应激障碍中被认为是失调的。 我们计划在PTSD和CC中使用NVNS作为探针，观察迷走神经调制对中枢神经系统的影响：1 神经回路在疼痛和疼痛预期刺激中的作用，以及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作为探测器，以获得以下试点数据：1) 外周炎症生物标志物和2)fMRI衍生的对疼痛的脑成像反应，以促进我们的 了解共病疼痛和创伤后应激障碍的基本病理生理学，并最终提供有针对性的 为患有疼痛和创伤后应激障碍的退伍军人提供基于神经调节的干预。我们将研究两组[(创伤后应激障碍，CC)， (都没有慢性疼痛诊断)]，在两种情况下(nVNS或Sham刺激)，超过三次 穴位(nVNS/Sham前)、(nVNS/Sham后7天)和治疗后1个月(治疗后1个月 NVNS/Sham)。这项建议的第一个目标是测量对nVNS的外周炎症反应 治疗以描绘基于外周炎症的治疗反应性的生物标记物概况 创伤后应激障碍和慢性阻塞性肺疾病中的NVNS。第二步是测量大脑区域对疼痛和疼痛预期的反应 NVNS治疗前后的刺激任务，以证明：1)治疗的神经图谱 对nVNS的反应性；2)创伤后应激障碍和CC中nVNS对疼痛的神经影响。参与者将 接受为期7天的nVNS/Sham试验，其中包括炎症生物标志物、神经成像工具、创伤后应激障碍症状 严重程度和功能生活质量在7天前和7天后进行评估。此外，创伤后应激障碍症状 严重程度和功能生活质量将在研究开始后一个月进行评估。Pre和Pre的直接对比 后nVNS/Sham将为nVNS的神经调节提供客观和敏感的评估，并奠定 为进一步研究创伤后应激障碍的神经调节作用奠定基础。这样的结果可能会提供额外的证据 因此，最终提供的治疗方法可以增强VA的临床实践指南。

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.