Neuroimaging abnormalities in major depressive disorder: effect of inflammation

个人简介(申请人提供)：我毕业于遗传学和心理学学士学位，并获得精神病学遗传学博士学位。我的博士工作是基于这样一个原则，即气质和神经认知功能可以作为中间性状或内表型，以便于识别易患双相障碍的遗传变异。随后，我在德里夫茨博士的指导下完成了NIMH的博士后研究，在那里我专注于PET和MRI，以期利用这些技术进行基因分析。我目前是桂冠脑研究所(LIBR)的助理教授，专注于弥合严重抑郁障碍(MDD)免疫功能障碍和神经成像异常之间的差距。炎症被认为是通过改变5-羟色胺的前体色氨酸(Trp)的分解，降低5-羟色胺水平，增加犬尿氨酸(KYN)和神经毒性KYN代谢物的合成，如3-羟基犬尿氨酸(3HK)和喹啉酸(Quin)，从而导致抑郁。推动这种代谢转向KYN合成的促炎细胞因子之一是白介素6(IL6)，这种作用部分地被抗炎细胞因子白介素10(IL10)所抵消。我提出的K01的目的是研究血浆中IL6、IL10、Trp/Kyn代谢物浓度与MDD的三个神经生理学相关性之间的关系：(A)杏仁核、海马体和周围ACC对情绪激动的面孔的血流动力学反应的异常模式，(B)海马体积减少，以及(C)周围扣带前皮质(ACC)体积和/或厚度的减少。还将进行额外的、通常测量的细胞因子：In？、IL-2、IL-4、IL-5、IL-1？、IL-8、TNF-和IL-12p70(下称珠阵列：BA细胞因子)的事后分析。杏仁核体积的减少也将在术后进行评估。将招募60名MDD患者和60名健康对照(HCS)。IL-6、IL-10和BA细胞因子的血浆浓度将用细胞因子珠阵列测定，色氨酸、KYN和3HK的浓度将用高效液相色谱(HPLC)测定。成像将在GE MR750 3T扫描仪上进行，带有32通道线圈。功能图像(体素大小=2.5 mm x 2.5 mm x 2.9 mm)将与解剖图像(体素大小=0.86 mm x 0.86 mm x 0.9 mm)共同配准，该图像将被用于获得由自由漫游得出的体积和皮质厚度测量结果。此外，高分辨率T1和T2图像(0.47 mm x 0.47 mm x 2.0 mm)将用于手动分割杏仁核以及海马区和ACC的亚区。在6对匹配的MDD患者和HCS中获得的试点数据支持我们的几个假设：(A)。与HCS患者相比，MDD患者的海马体更小，ACCs更薄，杏仁核、海马体和腹内侧PFC活性更大，对蒙面悲伤和快乐面孔的反应。(B)。MDD患者IL-6、3HK水平高于HCS，而IL-10水平低于HCS。(C)。较高的IL6浓度与较低的海马体和杏仁核体积，以及较大的对蒙面的悲伤和快乐的面孔的更大的左外ACC反应有关。相反，IL10浓度与海马体积和ACC厚度呈正相关。(D)。更高的3-HK水平与杏仁核体积和ACC厚度的减少以及右侧海马区对蒙面悲伤与快乐面孔的更大反应有关。(E)。Trp-Kyn比率与右侧杏仁核对悲伤和快乐面孔的反应减少呈负相关。该项目可能是向阐明情绪障碍的病理生理学机制迈出的初步一步，有可能促进针对这一途径的下一代抗抑郁药物的开发，以及用于识别MDD亚型患者的非侵入性免疫生物标志物的开发。这款K01应用程序旨在为我提供在神经免疫学和神经成像领域工作所需的培训，从而使我能够实现我的长期职业目标，即对情绪障碍的免疫学基础提供智力洞察，从而促进新型治疗方法的发展。(A)。我将发展免疫功能的实用知识，并了解细胞因子和色氨酸蛋白-kyn代谢对中枢神经系统神经炎症过程的影响。这次培训将在丹策博士和蒂格博士的指导下进行，并将包括访问这两个实验室，分别学习高效液相色谱和细胞因子阵列技术。(B)。在Bellgowan博士和Dlivts博士的指导下，我将精通fMRI技术和数据分析。与Bellgowan博士的“动手”工作将侧重于使用Afni进行实验设计和数据处理，而德里夫茨博士将强调在文献背景下出现的方法学问题。此外，我还将在培训的第二年和第三年参加Afni“训练营”和自由冲浪培训课程。(C)在德里夫茨博士的指导下，我将加深我对情绪障碍的神经生物学的知识，并将获得进一步的神经解剖学培训，使我能够更好地解释文献中报告的成像结果，并促进对海马区和ACC亚区的手动分割。(D)我将接受进一步的研究道德培训，并培养重要的“软技能”，如冲突管理、招聘、监督和指导教职员工和学生。

DESCRIPTION (provided by applicant): I graduated with a B.S. in both genetics and psychology and earned a Ph.D. in psychiatric genetics. My Ph.D. work was based on the principle that temperament and neurocognitive function could be used as intermediate traits or endophenotypes in order to facilitate the identification of genetic variants predisposing to bipola disorder. Subsequently, I completed a post-doctoral fellowship under the mentorship of Dr. Drevets at the NIMH where I focused on PET and MRI with a view to leveraging these techniques for genetic analyses. I am currently an assistant professor at the Laureate Institute for Brain Research (LIBR) focusing on bridging the gap between immune dysfunction and neuroimaging abnormalities in major depressive disorder (MDD). Inflammation is hypothesized to contribute to depression by altering the breakdown of tryptophan (TRP), the precursor of serotonin, reducing serotonin levels and increasing the synthesis of kynurenine (KYN) and neurotoxic KYN metabolites, such as 3-hydroxykynurenine (3HK), and quinolinic acid (QUIN). One of the pro-inflammatory cytokines that drives this metabolic shunt towards KYN synthesis is interleukin 6 (IL6), an effect that is partly countered by the anti-inflammatory cytokine, interleuin 10 (IL10). My aim for the proposed K01 is to examine the association between the plasma concentrations of IL6, IL10, TRP/KYN metabolites, and three neurophysiological correlates of MDD: (a) the abnormal pattern of hemodynamic response in the amygdala, hippocampus, and perigenual ACC to emotionally-valenced faces, (b) reductions in hippocampal volume, and (c) reductions in volume and/or thickness of the perigenual anterior cingulate cortex (ACC). A post-hoc analysis with additional, commonly measured cytokines: IN?, IL2, IL4, IL5, IL1¿, IL8, TNF¿, and IL12p70 (hereafter bead array: BA cytokines) will also be conducted. A reduction in amygdala volume will also be assessed post-hoc. Sixty MDD patients and 60 healthy controls (HCs) will be recruited. Plasma concentrations of IL6, IL10, and BA cytokines will be measured using cytokine bead arrays, while measurements of TRP, KYN, and 3HK will be obtained with high performance liquid chromatography (HPLC). Imaging will be conducted on a GE MR750 3T scanner with a 32-channel coil. Functional images (voxel size=2.5mm x 2.5mm x 2.9mm) will be coregistered to an anatomical image (voxel size =0.86mm x 0.86mm x 0.9mm), which will in turn be used to obtain FreeSurfer-derived volumetric and cortical thickness measurements. In addition, high resolution T1 and T2 images (0.47mm x 0.47mm x 2.0mm) will be used for manual segmentation of the amygdala and subregions of the hippocampus and ACC. Pilot data obtained in 6 matched pairs of MDD patients and HCs support several of our hypotheses: (a). The MDD patients had smaller hippocampi, thinner ACCs, and showed greater amygdala, hippocampal and ventromedial PFC activity in response to masked sad vs happy faces than HCs. (b). MDD patients showed higher levels of IL6 and 3HK, but lower levels of IL10 than HCs. (c). Higher concentrations of IL6 were associated with lower hippocampal and amygdala volume, and a greater left perigenual ACC response to masked sad vs happy faces. Conversely, IL10 concentrations appeared positively correlated with hippocampal volume and ACC thickness. (d). Higher levels of 3-HK were associated with reduced amygdala volume and ACC thickness, and a greater right hippocampal response to masked sad vs happy faces. (e). The TRP-KYN ratio was inversely associated with a reduced right amygdala response to sad vs happy faces. This project may constitute a preliminary step towards elucidating one of the pathophysiological mechanisms of mood disorders, potentially facilitating the development of next-generation antidepressant medications that target this pathway, as well as non-invasive immunological biomarkers for identifying patients with an "inflammatory" subtype of MDD. This K01 application is designed to provide me with the training needed to work at the interface of the neuroimmunology and neuroimaging fields, thus allowing me to achieve my long-term career goal of providing intellectual insight into the immunological basis of mood disorders, thereby promoting the development of novel treatments. (a). I will develop a working knowledge of immunological function and understand the impact of cytokines and TRP-KYN metabolism on neuroinflammatory processes in the CNS. This training will take place under the mentorship of Drs. Dantzer and Teague, and will incorporate visits to both labs to learn HPLC and cytokine array techniques, respectively. (b). I will become proficient in fMRI techniques and data analysis under the mentorship of Drs. Bellgowan and Drevets. "Hands-on" work with Dr. Bellgowan will focus on experimental design and data processing using AFNI while Dr. Drevets will emphasize methodological issues arising within the context of the literature. In addition, I will attend the AFNI "bootcamp" and FreeSurfer training course in years 2 and 3 of my training, respectively. (c) Under the mentorship of Dr. Drevets, I will deepen my knowledge of the neurobiology of mood disorders and will obtain further training in neuroanatomy, enabling me to better interpret imaging results reported in the literature and facilitating the manual segmentation of hippocampal and ACC subregions. (d) I will obtain further training in research ethics and develop important "softer skills" such as conflict management, and the recruitment, supervision, and mentoring of staff and students.