White matter and emotional and cognitive control in late-onset depression

描述（由申请人提供）：长期以来，人们一直认为与衰老相关的大脑变化会导致迟发性抑郁症（LOD）。我们认为，白色物质的微观结构异常和异常激活的情绪和认知控制领域的LOD的发展和持续的症状。据我们所知，拟议的翻译研究将是第一个专注于使用先进的多模态神经影像学方法的LOD机制。我们对控制网络的关注是基于以下观察：1）对来自负价无关刺激的干扰的敏感性（情绪控制）在抑郁症中可能特别突出; 2）难以在忽略无关刺激的情况下进行目标导向行为（认知控制）是抑郁症的一个主要特征，认知控制过程更易受年龄增长的影响; 3）认知控制的传统神经心理学测量的表现不佳与抑郁症的持续性有关，尽管抗抑郁药治疗。与NIMH RDoC项目的任务一致，即确定“电路-行为关系的临床相关模型”， 本项目的主要目的是利用功能性磁共振成像（fMRI）和扩散张量成像（DTI）对LOD患者进行检查，以确定情感和认知控制系统的功能障碍是否是与衰老相关的大脑异常导致LOD的机制。对于我们的主要假设，我们将集中在以下方面的作用：1）微结构白色物质（WM）异常（通过概率纤维束描记术测量）和情绪控制结构的激活在LOD的发展;和2）微结构WM异常和认知控制结构的激活在LOD的发展。对于我们的次要假设，我们将集中在微结构WM异常，激活控制结构和持久性LOD的作用，尽管治疗与SSRI。这些目标将在70名LOD患者和70名非抑郁症老年人中实现。LOD组将接受为期2周的单盲、安慰剂导入、精神药物洗脱期，结束时他们将完成MRI检查，包括fMRI和DTI。然后，患者将接受12周的艾司西酞普兰治疗，目标日剂量为20 mg。除了测试我们的假设外，该研究还可以探索性分析：1）WM高强度，控制系统激活以及LOD的发展和持续性之间的关系;以及2）治疗后控制网络激活与a的关系。基线激活和WM完整性和B. 12周时抑郁持续存在。我们希望通过对LOD的MRI研究，为抑郁症的神经回路机制提供新的信息。此外，LOD的结构和功能损伤的识别可以帮助临床仪器和有针对性的干预措施的开发。

DESCRIPTION (provided by applicant): It has been long held that aging-related brain changes contribute to late onset depression (LOD). We argue that white matter microstructural abnormalities and abnormal activation in the emotional and the cognitive control territories contribute to the development of LOD and to the persistence of its symptoms. To our knowledge, the proposed translational study would be the first to focus on mechanisms of LOD using advanced multimodal neuroimaging methods. Our focus on control networks is based on the following observations: 1) Susceptibility to interference from negatively-valenced irrelevant stimuli (emotional control) may be particularly salient in depression; 2) Difficulty engaging in goal-directed behavior while ignoring irrelevant stimuli (cognitive control) is a cardinal feature f depression and cognitive control processes are preferentially susceptible to advancing age; 3) Poor performance on a traditional neuropsychological measure of cognitive control is associated with persistence of depression despite antidepressant treatment. Consistent with the NIMH RDoC Project mandate to identify "clinically relevant models of circuitry- behavior relationships," the primary aim of this project is to use functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) in individuals with LOD to examine whether dysfunction of the emotional and cognitive control systems are mechanisms by which aging-related brain abnormalities contribute to LOD. For our primary hypotheses we will focus on the role of: 1) Microstructural white matter (WM) abnormalities (measured by probabilistic tractography) and activation of emotional control structures in the development of LOD; and 2) Microstructural WM abnormalities and activation of cognitive control structures in the development of LOD. For our secondary hypotheses, we will focus on the role of microstructural WM abnormalities, activation of control structures and the persistence of LOD despite treatment with an SSRI. The aims will be pursued in 70 patients with LOD and 70 non-depressed older adults. The LOD group will undergo a 2-week, single-blind, placebo lead-in, psychotropic washout phase at the end of which they will complete an MRI session that includes fMRI and DTI. Patients will then receive 12 weeks of escitalopram treatment at the target daily dose of 20 mg. In addition to testing our hypotheses, the study enables exploratory analyses of: 1) The relationships among WM hyperintensities, control system activations, and the development and persistence of LOD; and 2) Relationships of control network activation post-treatment to a. baseline activation and WM integrity and b. persistence of depression at 12 weeks. We expect this MRI study of LOD to offer novel information about the neural circuitry mechanisms of depression. In addition, the identification of structural and functional impairments of LOD can aid the development of clinical instruments and targeted interventions.