Circadian Rhythms and Sleep, Structural Neuroimaging and Depression in People with Multiple Sclerosis

项目总结 本申请表是关于导师研究科学家职业发展奖(K01)的申请。该奖项将提供 具有增强的技能和必要的培训的候选人，以建立一个研究计划，调查 伴有特殊疾病的中枢神经系统(CNS)自身免疫性疾病增加抑郁负担 关注多发性硬化症(MS)。患有多发性硬化症的人患精神疾病的风险明显更高， 包括抑郁症。据估计，多发性硬化症患者终生抑郁的患病率达到50%和 几乎是其他慢性病患者的两倍。抑郁也与过度的多发性硬化症有关 发病率和死亡率。然而，推动医疗保险负担增加的具体机制和风险因素 多发性硬化症患者的抑郁状态还没有得到很好的理解。拟议项目的目标是为应聘者提供 建立一个专注于了解神经生物学的独立项目所需的高级技能 多发性硬化症患者抑郁的机制将更好地为治疗和预防策略提供信息 风险人群。提出的综合、全面的培训计划结合了正规的课程作业、说教 来自导师的指导，实际操作的数据收集和分析会议，以及参加科学 研讨会和会议。主要培训目标包括：1)加深对抑郁症生物学的了解 为了更好地为风险和预防研究提供信息，2)在大量人群中评估抑郁症的经验- 基于研究的研究，3)应用结构神经成像分析的技能，作为更好地理解 与抑郁症状相关的神经解剖学变化。其他培训目标包括获得关键的 评估MS抑郁症的潜在风险上游风险因素的经验，特别是 应聘者将接受睡眠和昼夜节律生物学和评估方面的培训，这是两个相关的和 在生物学上可能导致多发性硬化症患者抑郁的因素这一全面的综合训练计划将 允许候选人利用来自正在进行的大型观察性研究的现有数据和基础设施 已经在10个站点招募了超过6554名多发性硬化症患者。标准化定量3-特斯拉大脑磁共振成像，抑郁 作为这项研究的一部分，至少每年都会获得症状和临床信息。她将测试是否 特定脑亚结构体积的纵向变化与抑郁症状的恶化相关 在患有多发性硬化症的人中(目标1)。此外，为了促进我们对看似合理的上游抑郁风险因素的理解， 她还将测试昼夜节律紊乱和睡眠障碍是否是抑郁症的潜在诱因 (可能通过改变大脑结构)在局部MS路径参与者的子集中(n=100； 目标2)。综上所述，这些研究的结果将使用强大的纵向设计得出，并可能 为了解患有多发性硬化症的人的抑郁症状如何演变提供了重要的见解。 重要的是，从拟议的奖励中获得的培训将使候选人成为一名独立的 具有进行高质量抑郁症研究所需技能的调查员，因为它与多发性硬化症患者有关。

PROJECT SUMMARY This application is for a Mentored Research Scientist Career Development Award (K01). The award will provide the candidate with enhanced skills and necessary training to build a research program that investigates the increased burden of depression in autoimmune diseases of the central nervous system (CNS) with a particular focus on multiple sclerosis (MS). People with MS are a markedly higher risk for psychiatric comorbidities, including depression. Estimates of lifetime prevalence of major depression in people with MS reach 50% and are nearly twice that of those with other chronic conditions. Depression is also linked with excess MS-associated morbidity and mortality. However, the specific mechanisms and risk factors driving the increased burden of depression in MS are not well-understood. The goal of the proposed project is to provide the candidate with advanced skills needed to establish an independent program focused on understanding neurobiological mechanisms of depression people with MS that will better inform treatment and prevention strategies in this high- risk population. The composite, comprehensive training plan proposed combines formal coursework, didactic instruction from her mentors, applied hands-on data collection and analysis sessions and attendance at scientific seminars and meetings. Primary training goals include 1) gaining a deeper understanding of depression biology to better inform studies of risk and prevention, 2) experience in the assessment of depression in large population- based research studies, 3) skills in applied structural neuroimaging analysis as tools to better understand neuroanatomical changes as they relate to depressive symptoms. Other training goals involve gaining critical experience in the evaluation of potential risk upstream risk factors for depression in MS. Specifically, the candidate will receive training in sleep and circadian rhythm biology and evaluation, which are two related and biologically plausible contributors to depression in MS. This comprehensive, composite training program will allow the candidate to leverage existing data and infrastructure from a large on-going observational study that has enrolled over 6,554 MS patients across 10-sites. Standardized quantitative 3-Tesla brain MRIs, depressive symptoms and clinical information are acquired at least annually as a part of this study. She will test whether longitudinal changes in specific brain substructure volumes are associated with depressive symptom worsening in people with MS (Aim 1). Further, to advance our understanding of plausible, upstream depression risk factors, she will also test if circadian rhythm disruption and sleep disturbance are potential contributors to depression (possibly mediated through alterations to brain structure) in a subset of local MS PATHS participants (n=100; Aim 2). Taken together, findings from these studies will be derived using a powerful longitudinal design and may provide important insight into understanding how depressive symptoms evolve in people with MS. The data and, importantly, the training garnered from the proposed award will allow the candidate to become an independent investigator with the skills needed to conduct high-quality depression research as it relates to people with MS.