Neural Substrates and Mechanisms Underlying Rumination in Depression

描述（由申请人提供）：本K01提案旨在提供所需的培训，以促进以下职业：(1)开发有助于我们理解抑郁症的计算模型；(2)确定了影响抑郁易感性和严重程度的神经回路；(3)识别、创造或改进针对抑郁症特定神经机制的治疗方法。为了实现他的目标，候选人提出了一个培训计划，以培养应用神经成像和计算建模技术的专业知识，专注于识别和瞄准抑郁症中驱动反刍的神经缺陷。反刍是抑郁症病因和维持的潜在机制，但在现有的治疗中尚未得到很好的理解或充分的针对性。抑郁反刍的很大一部分需要对抑郁的原因进行因果搜索，这通常会导致抑郁的个体检查他/她最紧迫的问题和关注，试图理解和解决它们。然而，这个过程并不能产生解决方案。因此，候选人将反刍的各个方面概念化为抑郁症患者试图解决问题的失败尝试。神经影像学在识别机制方面取得了可喜的成果，但主要集中在抑郁症的一组有限的特征上，通常不涉及解决问题的神经机制。为了进行这项必要的研究，候选人制定了详细的职业发展计划。该计划的重点是(1)扩大他目前在神经影像学评估方面的培训；(2)对其进行认知情感神经科学和干预研究范式的培训；(3)增强他在使用计算建模来理解精神病理学中的脑功能方面的知识。这种培训将通过教学课程、神经影像学研讨会、计算建模教程和临床干预研究培训来实现。还将通过不断的监督和与有关领域专家的协商促进培训。该培训将用于开展研究，具体目标是：(1)识别、验证和理解与反刍相关的神经回路；(2)识别抑制问题解决和驱动反刍的神经缺陷；(3)研究解决问题训练的潜力，以纠正抑郁症中驱动反刍的神经缺陷。拟议的培训和研究将在匹兹堡大学医学院的精神病学部门进行。精神科拥有几位世界知名的临床情感神经科学家，并隶属于国内首屈一指的认知神经基础研究中心之一。拟议的研究将分三个阶段进行，以实现其具体目标。在第一阶段，抑郁和健康的对照组参与者在进行功能磁共振成像（fMRI）时被诱导进行反刍。然后将研究促进解决问题的大脑区域之间的激活和交流的组间差异。随后，识别出的神经活动将通过将其与相关的行为结构（例如反刍的测量）联系起来进行验证。这些结果将有助于绘制潜在反刍的大脑区域，并指出驱动反刍处理的机制。在第二阶段，将创建一个计算模型来阐明抑郁症中解决问题能力差和反刍的机制。然后，这个模型将被用来预测抑郁症在解决问题时的神经缺陷。这些预测将通过观察抑郁和健康受试者在使用功能磁共振成像完成解决问题任务时的大脑活动来评估。已确定的问题解决缺陷背后的神经机制，假设驱动反刍，将通过检查这种缺陷模式与反刍处理过程中相同缺陷模式的关联程度来验证。这些结果将有助于确定抑郁症反刍的机制。在第三阶段，一部分抑郁参与者将被要求参与一项认知问题解决训练协议，该协议旨在针对已识别的神经缺陷。从基线评估来看，大脑活动的变化将通过对反刍和解决问题的后续fMRI评估来评估。如果成功，这些结果将表明一种直接针对抑郁症中驱动反刍的神经机制的方法，可以在未来的研究中充分发展为辅助治疗。综上所述，本研究旨在拓宽目前抑郁症神经病理生理学研究的重点，超越目前对快感缺乏和慢性抑郁情绪的标志物和机制的研究范围。目前的建议将通过成像任务来阐明抑郁症反刍的神经回路，这些任务特别激活了这些回路，并显示了它们与功能和机制变化的相关性。令人惊讶的是，我们对反刍的神经基础知之甚少。目前将抑郁症中的反刍概念化为一个被破坏的功能过程，这使得识别新的神经机制成为可能，而这些机制似乎不是当前治疗的目标。在未来的研究中，成功地识别和解决这些缺陷可能会为某些抑郁症患者提供持久的康复。

DESCRIPTION (provided by applicant): This K01 proposal is designed provide the training needed to facilitate a career that (1) develops computational models that aid in our understanding of depression; (2) identifies neural circuits that contribute to depression vulnerability and severity; and (3) identifies, creates, or refines treatments that target specific neural mechanisms of depression. To realize his goals the candidate has proposed a program of training to foster expertise in applying neuroimaging and computational modeling techniques to research focused on identifying and targeting neural deficits driving rumination in depression. Rumination is a potential mechanism underlying the etiology and maintenance of depression that is not well understood or adequately targeted in existing treatments. A significant portion of depressive rumination entails a causal search for the reasons one is depressed, that typically leads a depressed individual to examine his/her most pressing problems and concerns in an attempt to understand and solve them. However, this process does not lead to the generation of solutions. Hence, the candidate has conceptualized aspects of rumination as a depressed person's failed attempts to engage in problem-solving. Neuroimaging has produced promising results in identifying mechanisms, but has focused on a restricted set of features of depression generally not involving neural mechanisms of problem-solving. In order to carry out this needed research, the candidate has formulated a detailed career development plan. This plan focuses on (1) expanding his current training in neuroimaging assessment; (2) training him in the paradigms of cognitive affective neuroscience and intervention research; and (3) enhancing his knowledge of using computational modeling to understand brain functioning in psychopathology. This training will be achieved through didactic coursework, neuroimaging workshops, tutorials in computational modeling, and training in clinical intervention research. Training will also be facilitated through ongoing supervision and consultation with experts in relevant fields. This training will be used to conduct research that specifically aims to (1) identify, validate, and understand neural circuits associated with rumination; (2) identify neural deficits that inhibit problem-solving and drive rumination; and (3) examine the potential for problem-solving training to remediate neural deficits driving rumination in depression. The proposed training and research will be conducted in the Department of Psychiatry, at the University of Pittsburgh School of Medicine. The Department of Psychiatry houses several world-renowned clinical affective neuroscientists and is affiliated with one of the premier centers for understanding the neural basis of cognition in the country. The proposed research will take place in three stages to achieve its specific aims. In stage I, depressed and healthy control participants will be induced to ruminate while undergoing functional magnetic resonance imaging (fMRI). Group differences in activation and communication between brain regions facilitating problem-solving will then be examined. Subsequently, identified neural activity will be validated by associating it with relevant behavioral constructs, for example, measures of rumination. These results will facilitate the mapping of brain regions underlying rumination and point to mechanisms driving ruminative processing. In stage II, a computational model will be created to clarify the mechanisms underlying poor problem-solving and thus rumination in depression. This model will then be used to make predictions of neural deficits in depression during problem-solving. These predictions will be evaluated by observing brain activity in depressed and healthy subjects during the completion of a problem-solving task using fMRI. Identified neural mechanisms underlying deficits in problem-solving hypothesized to drive rumination will be validated by examining the degree to which this pattern of deficits is associated with the same pattern of deficits during ruminative processing. These results will facilitate the identification of mechanisms diving rumination in depression. In stage III, a subset of depressed participants will be asked to engage in a cognitive problem-solving training protocol designed to target the identified neural deficits. Change in brain activity from the baseline assessment will be evaluated using a follow-up fMRI assessment of rumination and problem-solving. If successful these results will suggest a means of directly targeting neural mechanisms driving rumination in depression that could be fully developed as an adjunctive treatment in future research. In summary, this proposal seeks to broaden the current focus of research into the neuropathophysiology of depression beyond its current scope of examining markers and mechanisms underlying anhedonia and chronic depressed mood. The current proposal will elucidate the neural circuits underlying rumination in depression by imaging tasks which specifically activate these circuits and showing their relevance to functioning and mechanistic change. Surprisingly very little is known regarding the neural substrates of rumination. The current conceptualization of rumination in depression as a disrupted functional process has allowed for the identification of novel neural mechanisms that do not appear to be targeted in current treatments. Successfully identifying and addressing these deficits may prove in future research to provide certain depressed individuals with lasting recovery.