Neurobiological Mechanisms of Stress in Youth with Chronic Widespread Pain

项目总结/摘要 儿童慢性广泛性疼痛（CWP）是一个严重的公共卫生问题，导致高水平的医疗保健利用和残疾。患有CWP的青少年还经常报告接触不良童年经历（ACE;虐待/忽视，暴力/冲突的家庭环境等）。并且一个重要的子集继续长期经历身体和心理社会损害。某些身心干预，如正念减压（MBSR）或冥想可能特别适合于患有CWP的青少年，因为它们已被证明可以调节压力引起的HPA轴，自主神经系统，心血管系统和大脑结构（例如，海马）。然而，目前尚不清楚这些目标是否会影响患有CWP的青年。初步研究表明，非稳态负荷（AL），或“磨损”的神经系统由于压力，可能有助于疼痛慢性化。同样，有证据表明，海马体是受压力影响最严重的大脑结构之一，在疼痛感知中起着重要作用。然而，迄今为止还没有研究检查AL和海马功能与CWP青年应激暴露的关系。身心干预，如正念减压或冥想是一个重要的和安全的治疗选择与CWP青年疼痛和压力的减少，并可能调节ACE的负面影响，所以有一个关键需要知道这些机制是否在这一人群。拟议的研究项目利用多因素生理和神经影像测量技术，以提高我们对这些机制在疼痛相关损害和对身心干预的反应中的潜在作用的理解。本次提交的目的是更好地表征AL，通过多因素复合评估，以及通过儿童CWP中的fMRI评估海马功能，作为身心干预的特定目标，可以优化治疗并提高依从性。这个K23奖的长期目标是为候选人建立一个独立的研究生涯，旨在进行机械知情的身心干预。选择慢性广泛性疼痛作为模型条件，因为它在儿科疼痛诊所中具有共性，并且与中枢致敏、高压力、心理障碍和功能障碍密切相关。主要培训目标是获得神经生物学测量和解释方面的专业知识，并利用当前的研究活动来补充这一提议，这将为未来作为独立研究者提交机械驱动的临床试验资助奠定基础。候选人将通过以下方式实现这一目标：1）在临床/研究环境中的指导，2）在压力的生理影响的神经生物学测量方面的实践培训，辅之以神经内分泌和功能磁共振成像测量的教学法，3）高级数据分析技术的指导和课程，4）利用心理社会实践活动和临床试验参与与拟议奖项的努力相结合，以及5）执行拟议的研究计划并提交独立研究者奖励申请。这些研究和培训将为R 01临床试验的开发提供必要的数据，该临床试验旨在测试患有CWP的青年对MBSR，冥想和其他非药物技术的反应的生理机制。

Project Summary/Abstract Pediatric chronic widespread pain (CWP) is a serious public health problem resulting in high levels of healthcare utilization and disability. Youth with CWP also frequently report exposure to adverse childhood experiences (ACEs; abuse/neglect, violent/conflictual home environment, etc.) and a significant subset continue to experience physical and psychosocial impairment long-term. Certain mind-body interventions such as mindfulness-based stress reduction (MBSR) or meditation may be particularly appropriate for youth with CWP as they have been shown to modulate stress-induced maladaptation of the HPA-axis, autonomic nervous system, cardiovascular system, and brain structure (e.g., hippocampus). However, it is currently unknown if these targets are affected in youth with CWP. Preliminary research indicates that allostatic load (AL), or “wear and tear” on the nervous system due to stress, may contribute to pain chronicity. Similarly, evidence suggests that the hippocampus, a brain structure that is among the most deleteriously affected by stress, plays a role in pain perception. However, no study to-date has examined AL and hippocampal functioning in relation to stress exposure in youth with CWP. Mind-body interventions such as MBSR or meditation are an important and safe therapy option for both pain and stress reduction in youth with CWP and may modulate the negative impact of ACEs, so there is a critical need to know if these mechanisms are engaged in this population. The proposed research project utilizes multifactorial physiological and neuroimaging measurement techniques to enhance our understanding of the potential role of these mechanisms in pain-related impairment and responsiveness to mind-body interventions over time. The aims of this submission are to better characterize AL, assessed via a multifactorial composite, and hippocampal functioning via fMRI in pediatric CWP as specific targets for mind-body interventions that can lead to treatment optimization and improved compliance. The long-term goal of this K23 award is for the candidate to establish an independent research career aimed at carrying out mechanistically informed mind-body interventions. Chronic widespread pain was selected as a model condition because of its commonality within pediatric pain clinics and strong association with central sensitization, high stress, psychological impairment, and functional disability. The primary training objectives are to acquire expertise in neurobiological measurement and interpretation and to leverage current research activities in complement to this proposal that will lay the foundation for future mechanistically driven clinical trial grant submissions as an independent investigator. The candidate will accomplish this through: 1) mentorship in a clinical/research environment, 2) hands-on training in the neurobiological measurement of the physiological effects of stress, complemented by didactics in neuroendocrine and fMRI measurement, 3) mentorship and coursework in advanced data analytic techniques, 4) leveraging psychosocial practice activities and clinical trial involvement in conjunction with effort on the proposed award, and 5) execution of the proposed research plan and submission of an independent investigator award application. These studies and training will provide the necessary data to inform the development of an R01 clinical trial designed to test the physiological mechanism(s) of response to MBSR, meditation, and other non-pharmacological techniques in youth with CWP.