Neural Substrates and Mechanisms Underlying Rumination in Depression

抑郁症沉思背后的神经基础和机制

基本信息

项目摘要

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.
描述(由申请人提供):这份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)确定导致抑郁症易感性和严重性的神经回路;以及(3)确定、创建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,这位候选人提出了一项培训计划,以培养将神经成像和计算建模技术应用于研究的专业知识,研究重点是识别和瞄准导致抑郁症沉思的神经缺陷。反思症是抑郁症的病因和维持的潜在机制,在现有的治疗方法中没有得到很好的理解或充分的靶向。抑郁沉思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人审视他/她最紧迫的问题和担忧,试图理解和解决这些问题。然而,这个过程并不会导致解决方案的产生。因此,候选人将沉思的方方面面概念化为抑郁的人尝试解决问题的失败。神经成像在识别机制方面取得了有希望的结果,但重点放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。为了开展这项必要的研究,应聘者制定了详细的职业发展计划。这项计划的重点是(1)扩大他目前在神经成像评估方面的培训;(2)培训他在认知情感神经科学和干预研究的范式;以及(3)增强他在精神病理学中使用计算建模来理解大脑功能的知识。这种培训将通过教学课程、神经成像研讨会、计算建模教程和临床干预研究培训来实现。还将通过持续监督和与相关领域的专家协商来促进培训。这项培训将被用来进行研究,其具体目标是:(1)识别、验证和理解与沉思相关的神经回路;(2)识别抑制问题解决和驱动沉思的神经缺陷;以及(3)检验解决问题培训的潜力,以补救抑郁症中驱动沉思的神经缺陷。拟议的培训和研究将在匹兹堡大学医学院的精神病学系进行。精神病学系拥有几位世界知名的临床情感神经科学家,并隶属于该国了解认知神经基础的主要中心之一。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,抑郁症和健康对照参与者将被诱导在接受功能磁共振成像(FMRI)的同时反省。然后将考察促进问题解决的大脑区域在激活和交流方面的群体差异。随后,识别出的神经活动将通过将其与相关的行为结构相关联来验证,例如,沉思的测量。这些结果将有助于绘制大脑潜伏沉思的区域图,并指出驱动反思性加工的机制。在第二阶段,将创建一个计算模型,以澄清问题解决能力差,从而导致抑郁的沉思的机制。然后,这个模型将被用来预测在解决问题的过程中抑郁症的神经缺陷。这些预测将通过观察抑郁症和健康受试者在完成问题解决任务期间的大脑活动来进行评估,方法是使用功能磁共振成像。通过检查这种缺陷模式与反思性加工过程中同样的缺陷模式相关联的程度,将验证被识别的潜在问题解决缺陷的神经机制,该缺陷模式被认为是驱动反省的。这些结果将有助于识别抑郁症潜水反省的机制。在第三阶段,一部分抑郁的参与者将被要求参与一项旨在针对已识别的神经缺陷的认知问题解决培训方案。大脑活动与基线评估相比的变化将使用后续的fMRI评估来评估沉思和解决问题。如果成功,这些结果将表明,一种直接针对抑郁症患者沉思的神经机制的方法,可以在未来的研究中作为一种辅助治疗方法充分开发出来。综上所述,这项建议旨在拓宽目前对抑郁症神经病理生理学的研究重点,超越其目前检查快感缺乏和慢性抑郁情绪的标记物和机制的范围。目前的提议将通过成像任务来阐明抑郁症沉思背后的神经回路,这些任务专门激活这些回路,并显示它们与功能和机制变化的相关性。令人惊讶的是,人们对沉思的神经基础知之甚少。目前将抑郁中的反思症概念化为一种被扰乱的功能过程,这使得目前的治疗方法中似乎没有针对的新的神经机制得以识别。成功识别和解决这些缺陷可能会在未来的研究中被证明为某些抑郁症患者提供持久的康复。

项目成果

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Neil Patrick Jones其他文献

Neil Patrick Jones的其他文献

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{{ truncateString('Neil Patrick Jones', 18)}}的其他基金

Neurodevelopment of Emotional Interference Resistance in Adolescence to Adulthood: A Multimodal Neuroimaging Approach
青春期至成年期情绪干扰抵抗的神经发育:多模式神经影像学方法
  • 批准号:
    10533518
  • 财政年份:
    2022
  • 资助金额:
    $ 13.99万
  • 项目类别:
Biological systems underlying the impact of potential threat on cognitive control in mood disorders
潜在威胁对情绪障碍认知控制影响的生物系统
  • 批准号:
    10430138
  • 财政年份:
    2018
  • 资助金额:
    $ 13.99万
  • 项目类别:
Biological systems underlying the impact of potential threat on cognitive control in mood disorders
潜在威胁对情绪障碍认知控制影响的生物系统
  • 批准号:
    9766892
  • 财政年份:
    2018
  • 资助金额:
    $ 13.99万
  • 项目类别:
Biological systems underlying the impact of potential threat on cognitive control in mood disorders
潜在威胁对情绪障碍认知控制影响的生物系统
  • 批准号:
    10203754
  • 财政年份:
    2018
  • 资助金额:
    $ 13.99万
  • 项目类别:
Neural Substrates and Mechanisms Underlying Rumination in Depression
抑郁症沉思背后的神经基础和机制
  • 批准号:
    8367232
  • 财政年份:
    2010
  • 资助金额:
    $ 13.99万
  • 项目类别:
Neural Substrates and Mechanisms Underlying Rumination in Depression
抑郁症沉思背后的神经基础和机制
  • 批准号:
    8197374
  • 财政年份:
    2010
  • 资助金额:
    $ 13.99万
  • 项目类别:
Neural Substrates and Mechanisms Underlying Rumination in Depression
抑郁症沉思背后的神经基础和机制
  • 批准号:
    8043401
  • 财政年份:
    2010
  • 资助金额:
    $ 13.99万
  • 项目类别:

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