The Relationships of Peripheral Inflammation and Reward-Related Brain Function with Anhedonia, Somatic Symptoms and Functional Impairment in Adolescence

工程 摘要/摘要 严重抑郁症(MD)是影响全球数百万人的主要残疾来源。尽管如此，30- 50%的抑郁人群对目前可用的治疗没有足够的反应。研究 提示低应答率可能源于炎症信号的升高和异常 奖励处理并不是目前可用的治疗方法所针对的。然而，两国的关系 诊断为MD的炎症和奖赏功能异常并不能一致地被检测到。新兴 研究将不一致的发现归因于可能的炎症和 奖赏相关的大脑功能异常。事实上，炎症和奖赏异常是有联系的。 快感缺乏，MD的一个基本特征，定义为对以前享受的兴趣或愉悦减少 活动，以及以严重的快感缺乏、躯体症状和功能性为特征的忧郁性MD 损害通常由奖励功能调节，而很少有证据支持这些异常 与认知症状(例如，消极认知)有关。这表明有必要研究一下 炎症和奖赏异常只与某些MD症状有关。此外，炎症可能 扩大奖赏功能障碍对这些症状的影响，因为它在改变奖赏相关的多巴胺能 音调和基底节功能。然而，很少有工作对这些说法进行检验。发育阶段也可能 导致关于炎症和奖赏功能与MD之间的联系的不一致的发现。青少年可能会 鉴于奖赏脑功能和炎症表型的快速变化，尤其容易受到攻击。因此， 这项拟议的研究试图验证炎症升高和奖赏减少与大脑相关的假说 单独的和相互作用的功能与快感缺乏、躯体症状和 在青春期脆弱的发育阶段，功能障碍多于认知症状。这个 拟议的研究将招募至少192名14-16岁的青少年，他们的特征奖励敏感度不同，他们已经登记参加了 外周炎性标志物与奖赏相关的神经激活和功能连接的评估 对于我的赞助商NIMH资助的R01，首发MD的前瞻性、纵向研究。一项培训计划已经完成 设计包括正式课程、研讨会、体验式学习和指导，以开发 申请人在情绪症状病理生理学、心理神经免疫学、神经成像和 数据分析是成为一名独立的临床神经学家所必需的。利用研究领域 检查炎症、奖赏相关脑功能和个体MD症状的标准视角，这 研究可以更深入地了解炎症和奖赏相关的异常在抑郁症中的作用 针对炎症和异常奖赏功能的干预的精神病理学和临床意义。 这项拟议的研究将在坦普尔大学的临床心理学博士项目中进行，该项目有一个 成功开展美国国立卫生研究院资助的研究和培训临床研究科学家的成功记录。 1

PROJECT SUMMARY/ABSTRACT Major depression (MD) is a major source of disability affecting millions of people worldwide. Nevertheless, 30- 50% of the depressed population does not respond sufficiently to currently available treatments. Research suggests that the low treatment response rate may stem from elevated inflammatory signaling and abnormal reward processing that are not precisely targeted by currently available treatments. However, relationships of inflammation and abnormalities in reward function with a MD diagnosis are not detected consistently. Emerging research attributes the inconsistent findings to possible symptom-specific effects of inflammation and abnormalities in reward-related brain function. Indeed, inflammation and reward abnormalities have been linked with anhedonia, a cardinal feature of MD defined by decreased interest or pleasure in previously enjoyable activities, and with melancholic MD characterized by severe anhedonia, somatic symptoms, and functional impairment commonly modulated by reward function, whereas little evidence supports these abnormalities' association with cognitive symptoms (e.g., negative cognitions). This suggests a need to examine whether inflammation and reward abnormalities are relevant to only some MD symptoms. Further, inflammation may amplify the effect of reward dysfunction on these symptoms, given its role in altering reward-related dopaminergic tone and basal ganglion function. However, little work has tested these claims. Developmental stage also may contribute to inconsistent findings on the links of inflammation and reward function with MD. Adolescents may be particularly vulnerable, given the rapid changes in reward brain function and inflammatory phenotype. Thus, the proposed study seeks to test the hypotheses that elevated inflammation and low reward-related brain function, separately, and in interaction, are more strongly associated with anhedonia, somatic symptoms, and functional impairment than cognitive symptoms, during the vulnerable developmental stage of adolescence. The proposed study will recruit at least 192 14-16 year-olds varying in trait reward sensitivity who have enrolled in an assessment of peripheral inflammatory markers and reward-related neural activation and functional connectivity for my sponsor's NIMH-funded R01, prospective, longitudinal study of first-onset MD. A training plan has been designed that consists of formal coursework, workshops, experiential learning, and mentorship to develop the applicant's expertise in the pathophysiology of mood symptoms, psychoneuroimmunology, neuroimaging, and data analysis necessary to become an independent clinical neuroscientist. Utilizing the Research Domain Criteria perspective to examine inflammation, reward-related brain function, and individual MD symptoms, this study can yield greater insight into the role of inflammation and reward-related abnormalities in depressive psychopathology and clinical implications for interventions targeting inflammation and abnormal reward function. The proposed study will take place in Temple University's clinical psychology Ph.D. program, which has a successful track record of conducting impactful NIH-funded research and training clinical research scientists. 1