Causal brain mechanisms of value-based attentional capture in depression

这是为Colleen Mills-Finnerty博士颁发的退伍军人管理职业发展奖2提案， 题为“抑郁症中基于价值的注意力捕获的因果大脑机制”。这个项目的目标是 为了了解奖赏注意敏感度降低背后的因果脑回路机制 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，目前的治疗方法疗效有限。此外，TMS是FDA批准的一种治疗 抑郁症，但其治疗症状的机制尚不清楚。因此，更好地 对引起行为异常和症状的回路异常的理解 抑郁是需要的，以摒弃有针对性的、神经生物学信息的经颅多普勒超声干预的发展。 对奖赏的注意敏感性在视觉知觉领域得到了广泛的研究。与奖励相关的刺激 (例如，金钱、积极的社会反馈)在任务期间吸引注意力(即，分散注意力)，即使在 奖赏价值与表现无关，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，抑郁症患者的VBAC在行为上是缺失的；然而， 研究已经解决了导致这一过程的生物学基础。了解VBAC功能障碍 抑郁可能是奖赏敏感度降低和奖赏学习之间的一个关键缺失环节 在抑郁症中被广泛观察到的缺陷，因此需要检验的中心假设是对 抑郁症患者的奖赏刺激与注意和记忆整合的回路机制失效有关。 主观价值。目前的研究目标是：1)在脑神经成像过程中对VBAC的反应进行计算建模 健康的退伍军人；2)在神经成像过程中对患有抑郁症的退伍军人的VBAC缺陷进行计算建模；3) 使用脑刺激来探索导致健康退伍军人VBAC的原因电路机制， 这条电路在抑郁症中的模型故障。CDA2奖将允许Mills-Finnerty博士获得 精通1)模拟行为和脑功能的计算方法；2)使用脑刺激 作为一种因果干预，以改变行为并了解精神病人群中的脑回路功能障碍； 3)抑郁症状的临床研究评估；4)专业性的手稿/资助写作 发展和负责任的研究行为。该项目的培训和研究将在 退伍军人事务部帕洛阿尔托大学和斯坦福大学，这两所大学都为 完成提议的工作。PI计划通过以下方式熟练掌握建议书领域：1)教程和 与导师的会议；2)关于神经回路和建筑内信息流建模的密集研讨会 计算行为模型；3)正式课程；4)出席专业会议；5)实用 将技能应用于研究数据；以及6)有计划地提交拨款申请和手稿。 这项拟议工作的见解将提高我们对VBAC背后的大脑过程的理解， 这将有助于从重要的机械学角度深入研究脑神经回路功能障碍的一个方面 抑郁症。该项目旨在通过脑刺激来引导有针对性的抑郁症干预 提高抑郁症退伍军人对奖励的注意敏感度。这种方法将构成一种新的 TMS治疗的范例及其潜在应用于其他影响奖赏功能的障碍，如 强迫症、成瘾和抑郁症与神经系统疾病相关，如 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.