An Integrative Examination of Brain Structure and Function in Major Depression

6.项目摘要/摘要 严重抑郁障碍(MDD)是最常见的精神疾病之一，影响多达20%的美国人口。然而，这种疾病的神经生物学基础尚未阐明。对抑郁症患者的结构神经成像研究记录了膝下部前额叶皮质(PFC)、背侧PFC和杏仁核的神经解剖异常，这些都是情绪调节网络的已知组成部分。然而，这篇文献的发现是混合的，一些但不是所有的研究人员报告了这些结构的体积减少。此外，这些异常可能与下丘脑-垂体-肾上腺轴(HPA)轴的调节失调有关，HPA轴是一种神经内分泌系统，当像MDD一样过度反应时，会导致糖皮质激素皮质醇的高水平和可能的神经毒性水平。这项研究的目标是使用结构磁共振结合自我报告测量、功能神经成像评估、HPA轴反应性指标和基因分型来评估被诊断为MDD的个体的大脑结构和功能异常。具体目标包括(1)使用新开发的灰质厚度测量工具评估MDD患者是否存在区域性神经解剖异常；以及(2)检查大脑结构中特定疾病的变化、HPA轴失调和杏仁核激活水平之间的关系。杏仁核是一种边缘结构，接受直接的抑制性皮质输入。为了实现这些目标，所有参与者都将接受功能和结构神经成像。结构磁共振数据将被处理，以提供沿皮质表面的每个点的皮质灰质的厚度测量。为了评估HPA轴的反应性，将在执行实验室应激任务时测量唾液皮质醇水平。皮质灰质厚度和皮质醇之间的关联将在皮质表面的每个点进行检查，以评估皮质区域的结构完整性是否在一定程度上依赖于HPA轴的失调，从而是否与频繁发生高皮质醇的易感性有关。将使用唾液DNA和自我报告措施进行额外的分析，以检查大脑结构和神经内分泌功能的相互作用是否受到遗传因素(5-羟色胺转运体基因多态)和环境因素(创伤史)的影响。最后，为了检验MDD患者杏仁核激活增强是否与皮质厚度有关，将对fMRI数据进行处理，以提供该区域的信号变化百分比，作为与局部灰质分布关联的协变量。这些措施之间的负关联将被研究，分析将解决杏仁核的调节，以及在更广泛意义上的影响，是否依赖于前额叶灰质的完整性，以及这个前额叶区域所伴随的抑制/执行功能。该研究计划将为申请者提供几种新方法的培训，包括收集和解释遗传、神经内分泌和事件相关的功能磁共振数据，以及MDD的诊断和临床评估。

6. Project Summary/Abstract Major Depressive Disorder (MDD) is among the most prevalent of psychiatric disorders, affecting as many as 20% of the American population. Yet, the neurobiologic basis of this disorder has not been elucidated. Structural neuroimaging studies of depressed individuals have documented neuroanatomic abnormalities in subgenual prefrontal cortex (PFC), dorsal PFC, and amygdala, known components of emotion regulatory networks. Findings from this literature, however, are mixed, with some, but not all investigators reporting volumetric reductions in these structures. Further, it is possible that these abnormalities may relate to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine system that, when hyperreactive as in MDD, results in high and likely neurotoxic levels of the glucocorticoid hormone, cortisol. The goal of this research is to assess abnormalities in brain structure and function in individuals diagnosed with MDD using structural MRI in conjunction with self-report measures, functional neuroimaging assessments, indicators of HPA-axis reactivity, and genotyping. Specific goals include (1) assessing whether there are regionally specific neuroanatomic abnormalities in MDD patients using newly developed tools for measuring gray matter thickness; and (2) examining associations among disease-specific alterations in brain structure, HPA-axis dysregulation, and activation level of the amygdala, a limbic structure that receives direct inhibitory cortical input. To achieve these objectives, all participants will undergo functional and structural neuroimaging. Structural MRI data will be processed to provide thickness measurements of cortical gray matter at each point along the cortical surface. To assess HPA-axis reactivity, salivary cortisol levels will be measured during the performance on a laboratory stress task. The association between cortical gray matter thickness and cortisol will be examined at each point along the cortical surface to assess whether structural integrity of cortical regions is, in part, dependent on HPA-axis dysregulation and, thus, whether it is related to susceptibility to becoming frequently hypercortisolemic. Additional analyses examining whether the interaction of brain structure and neuroendocrine function is influenced by genetic (serotonin transporter gene polymorphisms) and environmental (history of trauma) factors will be conducted using salivary DNA and self-report measures. Finally, to examine whether heightened amygdala activation in MDD individuals is related to cortical thickness, fMRI data will be processed to provide percent signal change in this region for use as a covariate for linkage with local gray matter distribution. Negative associations between these measures will be examined, and analyses will address whether regulation of the amygdala, and in a broader sense affect, is dependent on prefrontal gray matter integrity and on the inhibitory/executive functions that this prefrontal region subserves. This program of research will provide the applicant with training in several new methodologies, including the collection and interpretation of genetic, neuroendocrine, and event-related fMRI data, as well as in the diagnosis and clinical assessment of MDD.