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

描述(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，白质微结构异常和情绪和认知控制区的异常激活有助于LOD的发展及其症状的持续。据我们所知，这项拟议的翻译研究将是第一个利用先进的多模式神经成像方法关注LOD机制的研究。我们对控制网络的关注基于以下观察：1)对负价无关刺激(情绪控制)干扰的敏感性在抑郁症患者中可能特别显著；2)难以从事目标定向行为而忽略无关刺激(认知控制)是抑郁症的基本特征，认知控制过程更容易受到年龄的影响；3)在传统的认知控制神经心理学测量指标上表现不佳与抑郁症的持久性有关，尽管接受了抗抑郁药物治疗。与NIMH RDoC项目的任务一致，以确定“电路-行为关系的临床相关模型”， 该项目的主要目的是在LOD患者中使用功能磁共振成像(FMRI)和扩散张量成像(DTI)来研究情绪和认知控制系统的功能障碍是否是与衰老相关的脑异常导致LOD的机制。对于我们的主要假设，我们将集中在以下方面：1)微结构白质(WM)异常(通过概率纤维束成像测量)和情绪控制结构在LOD发展中的激活；以及2)微结构WM异常和认知控制结构在LOD发展中的激活。对于我们的第二个假设，我们将重点放在微结构WM异常的作用，控制结构的激活和LOD的持久性，尽管使用SSRI治疗。这些目标将在70名LOD患者和70名非抑郁症老年人中进行。LOD组将经历为期两周的单盲、安慰剂引导、精神药物淘汰阶段，在此阶段结束时，他们将完成包括功能磁共振成像和DTI的MRI疗程。然后，患者将接受12周的艾司西普兰治疗，目标剂量为每天20毫克。除了验证我们的假说，这项研究还能够探索性地分析：1)WM高信号、控制系统激活和LOD的发展和持续之间的关系；以及2)治疗后控制网络激活与A.基线激活和WM完整性以及B.12周抑郁持续的关系。我们期望这项LOD的MRI研究能为抑郁症的神经回路机制提供新的信息。此外，识别LOD的结构和功能损害有助于临床仪器和靶向干预的发展。

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.