An Integrative Examination of Brain Structure and Function in Major Depression

描述（由申请人提供）： 重度抑郁症（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影像学研究已经证实了膝下前额叶皮层（PFC）、背侧PFC和杏仁核（已知的情绪调节网络组成部分）的神经解剖学异常。然而，该文献的结果是混合的，一些但不是所有的研究者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（HPA）轴的失调有关，HPA轴是一种神经内分泌系统，当如MDD中反应过度时，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。本研究的目的是评估异常的大脑结构和功能诊断为MDD的个人使用结构MRI结合自我报告的措施，功能性神经影像学评估，HPA轴反应性的指标，和基因分型。具体目标包括（1）使用新开发的测量灰质厚度的工具评估MDD患者是否存在区域特异性神经解剖学异常;（2）检查疾病特异性脑结构改变、HPA轴失调和杏仁核激活水平之间的关联，杏仁核是一种接受直接抑制性皮质输入的边缘系统结构。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。将对结构MRI数据进行处理，以提供沿皮质表面沿着每个点的皮质灰质厚度测量值。为了评估HPA轴反应性，将在实验室应激任务执行期间测量唾液皮质醇水平。将在沿皮质表面的每个点沿着检查皮质灰质厚度和皮质醇之间的关联，以评估皮质区域的结构完整性是否部分依赖于HPA轴失调，从而评估其是否与变得频繁皮质醇过多的易感性相关。将使用唾液DNA和自我报告措施进行其他分析，检查大脑结构和神经内分泌功能的相互作用是否受遗传（5-羟色胺转运蛋白基因多态性）和环境（创伤史）因素的影响。最后，为了检查MDD个体中杏仁核激活是否与皮质厚度有关，将处理fMRI数据以提供该区域的信号变化百分比，以用作与局部灰质分布联系的协变量。这些措施之间的负相关性将被检查，分析将解决杏仁核的调节，并在更广泛的意义上影响，是否依赖于前额叶灰质的完整性和抑制/执行功能，这前额叶区subserve。该研究计划将为申请人提供几种新方法的培训，包括遗传，神经内分泌和事件相关fMRI数据的收集和解释，以及MDD的诊断和临床评估。

DESCRIPTION (provided by applicant): 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 hyper- reactive 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.