Neurobiological Mechanisms of Stress in Youth with Chronic Widespread Pain

项目摘要/摘要 儿科慢性广泛性疼痛(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率和残疾。患有CWP的青少年也经常报告接触过不良的童年经历(A级；虐待/忽视、暴力/冲突的家庭环境等)。而且有很大一部分人继续经历长期的身体和心理社会损伤。某些身心干预措施，如基于正念的减压(MBSR)或冥想，可能特别适合患有CWP的青少年，因为它们已被证明可以调节应激导致的HPA轴、自主神经系统、心血管系统和大脑结构(如海马体)的适应不良。然而，目前尚不清楚这些目标是否会在患有CWP的青年中受到影响。初步研究表明，非稳态负荷(AL)，或由于压力对神经系统的“磨损”，可能导致慢性疼痛。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，它在痛觉中扮演着重要角色。然而，到目前为止，还没有研究研究AL和海马体功能与患煤工尘肺的青年应激暴露的关系。心身干预，如MBSR或冥想，对于患有CWP的青年患者来说是一种重要且安全的治疗选择，可以减轻疼痛和压力，并可能调节ACE的负面影响，因此迫切需要了解这些机制是否参与了这一人群。拟议的研究项目利用多因素生理和神经成像测量技术来加强我们对这些机制在疼痛相关损害中的潜在作用的理解，以及随着时间的推移对心身干预的反应。这份意见书的目的是更好地描述通过多因素综合评估的AL和通过功能磁共振成像在儿童CWP中作为心身干预的特定目标的海马区功能，从而能够导致治疗优化和依从性的提高。这个K23奖项的长期目标是让候选人建立一个独立的研究生涯，旨在进行机械信息的心身干预。慢性广泛性疼痛因其在儿科疼痛临床中的共性以及与中枢敏感化、高应激、心理损伤和功能障碍的强烈关联而被选为模型条件。主要的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项建议，这将为未来作为独立调查者提交机械驱动的临床试验拨款奠定基础。候选人将通过以下方式实现这一目标：1)在临床/研究环境中进行指导；2)在应激的生理效应的神经生物学测量方面进行实践培训，辅之以神经内分泌和功能磁共振测量方面的教学；3)在高级数据分析技术方面的指导和课程工作；4)结合拟议奖项的努力，利用心理社会实践活动和临床试验参与；以及5)执行拟议的研究计划并提交独立调查员奖项申请。这些研究和培训将提供必要的数据，为R01临床试验的开发提供信息，该试验旨在测试青年煤工尘肺患者对MBSR、冥想和其他非药物技术的反应的生理机制(S)。

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.