抑郁症患者下丘脑神经影像学征象及其意义

The hypothalamus is one of the key brain structures involved in the pathophysiology of depression, and its abnormal activity is regarded as a final common pathway to the genesis of depression. Surprisingly, no systematic neuroimaging investigation focusing on in vivo human hypothalamus has yet been conducted in this specific population. This project aims to fill this gap, by measuring structural and functional alterations of the hypothalamus in patients with major depressive disorder in comparison with matched healthy control subjects. We will use magnetic resonance imaging techniques to characterize local activity of this nucleus and its functional connectivity in resting state, gray matter density/volume and white matter integration, and its structural connectivity to the hippocampus and amygdala. Serum level of corticotrophin-releasing factor (CRF), scores of stressful life events and the severity of depressive symptoms will also be measured. The patients group will be re-assessed after their treatments. We expect (1) to identify some specific abnormal imaging features of the hypothalamus by comparisons of the neuroimaging data between patients and control groups, (2) to validate the stability of these abnormal imaging features by a comparison of the neuroimaging data before and after treatments, and (3) to establish the relationships between the abnormal hypothalamic imaging features and the levels of stress response by correlational analysis of the imaging data and CRF data as well as stressful life events data. This project is the first multimodality MRI study that systematically exams structural and functional abnormalities of the hypothalamus in depression. The study is directly relevant to the early recognition and objective diagnosis of depression, and will be helpful for the understanding of the pathogenesis of depressive disorders.

下丘脑是参与抑郁症发病机制的关键脑结构，其异常活动被认为是抑郁症形成的最终共同通路，但迄今未见对抑郁症病人活体下丘脑深入系统的影像学研究。为此，本项目拟使用磁共振成像技术全面探测重性抑郁症患者和匹配健康志愿者下丘脑静息态表现、静息态功能连接、灰质密度、白质完整性、下丘脑与海马的结构连接、下丘脑与杏仁核的结构连接，分别使用生化和行为学手段测定两组血清促皮质激素释放因子（CRF）浓度、应激性生活事件负荷和抑郁症状严重程度，患病组在治疗后再次测量上述指标。拟通过对组间影像学数据的比较，找出患者下丘脑异常的结构特征和功能特征；通过对患者治疗前后影像学数据的比较，考察患者下丘脑异常征象的稳定性；通过对影像学数据与CRF及生活事件数据的相关分析，考察患者下丘脑异常征象与应激的关系。本项目是首次系统地探测抑郁症下丘脑结构和功能异常，研究结果对抑郁症的早期识别和客观诊断、对抑郁症的病理机制探索具有重要价值

下丘脑与抑郁症（MDD）关系的既往研究缺乏来自患者活体下丘脑异常的直接证据。本项目首次运用多模态影像学手段对MDD患者活体下丘脑的影像学特征进行直接探索和全面考察，以MDD患者和健康对照者为研究对象，分别在治疗前后采集其汉密尔顿抑郁量表（HAMD）等行为数据和磁共振影像（MRI）数据及生理生化数据。本项目的部分数据分析显示出有趣的结果。.1）治疗前MDD患者的下丘脑与前额叶-边缘网络（PLN）内的额中回、内侧额上回、前扣带皮层（ACC）等脑区之间的功能连接（FC）显著下降，下丘脑与PLN内的额中回、内侧额上回等脑区之间的FC与HAMD分值呈显著正相关，说明治疗前抑郁症患者下丘脑与PLN之间的功能活动有明显异常改变，且这些异常改变与抑郁症状严重程度相关，提示下丘脑与PLN之间功能的异常改变可能与抑郁症的发生和发展有密切关系。.2）治疗前MDD患者的下丘脑与右侧岛叶和颞叶的FC显著下降。以下丘脑FC数据构建的下丘脑功能网络为特征进行机器学习识别，发现机器学习对MDD患者与健康对照者识别的准确率为92%。表明下丘脑可能是根据静息态fMRI数据识别MDD患者的关键脑区。.3）抗抑郁治疗三月后，抑郁症患者左侧下丘脑与左侧颞上回及颞中回的FC比治疗前显著增强，右侧下丘脑与小脑的FC比健康对照者显著增强，左侧下丘脑与小脑、左侧丘脑、海马旁回等脑区的FC比健康对照者显著增强，治疗后抑郁症患者左侧下丘脑与小脑、颞中回、额上回等脑区的FC与抑郁程度呈正相关。表明下丘脑与其他脑区之间的FC在治疗前后的变化可能与MDD的恢复有关，测量这些变化可用于评估抗抑郁药的疗效。.该项目的成果目前有已发表论文两篇、待发表论文至少六篇。有四篇摘要在学术会议上发表，四名研究生在基金的支持下得到了良好的培训获得硕士学位。本项目获得的数据量巨大，需进一步从不同角度和方面对所有数据进行分析，以期发现更多有价值的结果。.总之，本项目在MDD患者活体发现的下丘脑异常可为MDD的客观诊断提供依据，并有助于更好地理解MDD背后的病理生理机制。