Causal brain mechanisms of value-based attentional capture in depression

这是一个退伍军人管理局职业发展奖2建议科琳米尔斯芬纳蒂，博士， 题目是“抑郁症中基于价值的注意力捕获的大脑机制”这个项目的目标是 为了了解大脑回路中对奖励的注意力敏感度降低的因果机制， 使用计算建模、神经成像和经颅磁刺激治疗抑郁症的退伍军人 （TMS）。这是一个重要的研究领域，因为尽管抑郁症是导致残疾的主要原因， 在世界范围内，目前的治疗效果有限。此外，TMS是FDA批准的治疗方法， 抑郁症，但其治疗症状的机制仍不清楚。因此， 了解引起行为异常和症状的电路异常， 抑郁症需要摒弃有针对性的，神经生物学知情的TMS干预措施的发展。 在视觉感知领域，对奖赏的注意敏感性得到了充分的研究。与奖励相关的刺激 (e.g.金钱，积极的社会反馈）吸引注意力（即，作为一个分心），即使在任务期间， 奖励价值与绩效无关，这是一种被称为基于价值的注意捕获（VBAC）的注意偏差。 更有限的证据表明，VBAC在抑郁症患者中是行为缺失的;然而， 研究已经探讨了造成这一过程的生物学基础。了解VBAC功能障碍 是奖励敏感性降低和奖励学习之间潜在的关键缺失环节 在抑郁症中广泛观察到的缺陷，因此要测试的中心假设是， 抑郁症中的奖励刺激与注意力整合的电路机制失败有关， 主观价值目前的研究旨在1）在神经成像过程中对VBAC反应进行计算建模， 健康退伍军人; 2）在神经成像过程中患有抑郁症的退伍军人的计算模型VBAC缺陷; 3） 使用脑刺激来探测健康退伍军人中负责VBAC的因果电路机制， 在抑郁症中模拟这种电路的故障。这个CDA 2奖将使米尔斯-芬纳蒂博士获得 熟练掌握1）建模行为和大脑功能的计算方法; 2）使用大脑刺激 作为改变行为和了解精神病人群脑回路功能障碍的因果干预; 3)抑郁症症状的临床研究评估;和4）手稿/赠款写作，专业 发展和负责任的研究行为。该项目的培训和研究将在 无论是弗吉尼亚州帕洛阿尔托大学和斯坦福大学，这提供了良好的智力和物理资源， 完成拟议的工作。PI计划通过以下方式熟练掌握提案领域：1）教程和 与导师的会议; 2）关于神经回路和建筑中建模信息流的密集研讨会 行为的计算模型; 3）正式课程; 4）参加专业会议; 5）实践 应用技能研究数据;和6）计划提交赠款申请和手稿。 从拟议的工作中获得的见解将提高我们对VBAC背后的大脑过程的理解， 这将有助于重要的机制洞察一个欠研究方面的电路功能障碍， 萧条该项目旨在通过脑刺激进行有针对性的抑郁干预， 增加抑郁症退伍军人对奖励的注意力敏感度。这种做法将构成一种新的 TMS治疗的范例，可能应用于影响奖励功能的其他疾病，如 如强迫症、成瘾和与神经系统疾病相关的抑郁症， 中风和帕金森氏症。

This is a Veteran's Administration Career Development Award 2 proposal for Colleen Mills-Finnerty, Ph.D., entitled “Causal brain mechanisms of value-based attentional capture in depression.” The goal of this project is to understand causal brain circuit mechanisms underlying diminished attentional sensitivity to reward in veterans with depression using computational modeling, neuroimaging, and transcranial magnetic stimulation (TMS). This is an important area for study because although depression is a leading cause of disability worldwide, current treatments have limited efficacy. Additionally, TMS is an FDA-approved treatment for depression, but the mechanism by which it works to remediate symptoms remains unclear. Therefore, better understanding of the circuit abnormalities that give rise to behavioral abnormalities and symptoms of depression is needed to spurn development of targeted, neurobiologically informed TMS interventions. Attentional sensitivity to reward is well-studied in the field of visual perception. Stimuli associated with rewards (e.g. money, positive social feedback) capture attention (i.e., serve as a distraction) during tasks even when reward value is not relevant to performance, an attentional bias called value-based attentional capture (VBAC). More limited evidence suggests that the VBAC is behaviorally absent in patients with depression; however no studies have addressed the biological underpinnings causal to this process. Understanding VBAC dysfunction in depression is potentially a critical missing link between reduced reward sensitivity and reward learning deficits widely observed in depression, and therefore the central hypothesis to be tested is that insensitivity to reward stimuli in depression is related to failures of circuit mechanisms underlying integration of attention and subjective value. The current study aims to 1) computationally model VBAC response during neuroimaging in healthy veterans; 2) computationally model VBAC deficits in veterans with depression during neuroimaging; 3) use brain stimulation to probe the causal circuit mechanisms responsible for VBAC in healthy veterans, to model failures of this circuitry in depression. This CDA2 award would allow Dr. Mills-Finnerty to gain proficiency in 1) computational approaches to modeling behavior and brain function; 2) use of brain stimulation as a causal intervention to change behavior and understand brain circuit dysfunction in psychiatric populations; 3) clinical research assessment of depression symptoms; and 4) manuscript/grant writing, professional development, and responsible conduct of research. Training and research for the project will be conducted at both the VA Palo Alto and Stanford University, which offer excellent intellectual and physical resources to complete the proposed work. The PI plans to gain proficiency in proposal domains through: 1) tutorials and meetings with mentors; 2) intensive workshops on modeling information flow within neural circuits and building computational models of behavior; 3) formal coursework; 4) attendance of professional meetings; 5) practical application of skills to research data; and 6) planned submission of grant applications and manuscripts. Insights from the proposed work will improve our understanding of the brain processes underlying VBAC, which will contribute important mechanistic insight to an understudied aspect of circuit dysfunction in depression. This project is intended to lead to a targeted depression intervention using brain stimulation to increase attentional sensitivity to reward in veterans with depression. This approach would constitute a new paradigm for TMS treatment with potential application to other disorders that impact reward functioning, such as obsessive-compulsive disorder, addiction, and depression associated with neurological conditions such as stroke and Parkinson's disease.