Neuroimaging abnormalities in major depressive disorder: effect of inflammation

重度抑郁症的神经影像学异常：炎症的影响

• 批准号: 8544495
• 负责人: Jonathan Savitz
• 金额: $ 18.14万
• 依托单位: LAUREATE INSTITUTE FOR BRAIN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544495
• 关键词: Affect; Amygdaloid structure; Anterior; Anti-Inflammatory Agents; Anti-inflammatory; Antidepressive Agents; Award; Biological; Biological Markers; Brain; Catabolism; Conflict (Psychology); Data; Data Analyses; Development; Disease; Doctor of Philosophy; Emotional; Experimental Designs; Face; Fellowship; Functional Imaging; Functional Magnetic Resonance Imaging; Future; Gene Expression; Genetic; Goals; High Pressure Liquid Chromatography; Hippocampus (Brain); IL2 gene; IL4 gene; IL5 gene; IL8 gene; Image; Immune System Diseases; Immune system; Inflammation; Inflammatory; Institutes; Interleukin-6; Knowledge; Kynurenic Acid; Kynurenine; Lead; Learning; Left; Literature; Magnetic Resonance Imaging; Major Depressive Disorder; Manuals; Masks; Measurement; Measures; Mediating; Mental Depression; Mentors; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Molecular; Molecular Abnormality; Molecular Target; Mood Disorders; National Institute of Mental Health; Neuroanatomy; Neurobiology; Neurocognitive; Neurotoxins; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Plasma; Positioning Attribute; Positron-Emission Tomography; Postdoctoral Fellow; Process; Psychology; Quinolinic Acid; Recruitment Activity; Reporting; Research Ethics; Resolution; Series; Serotonin; Shunt Device; Signal Transduction; Structure; Students; Subgroup; Supervision; T-Lymphocyte; TNF gene; Techniques; Temperament; Testing; Thick; Training; Tryptophan; Tryptophan 2,3 Dioxygenase; Visit; Work; base; blood oxygenation level dependent response; brain research; career; cingulate cortex; computerized data processing; cytokine; design; emotional stimulus; endophenotype; genetic analysis; genetic variant; hemodynamics; high risk; insight; interest; monocyte; neuroimaging; neuroimmunology; neurophysiology; neurotoxic; next generation; novel; peripheral blood; professor; psychogenetics; public health relevance; response; skills; trait

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.

描述（由申请人提供）：我毕业于学士学位在遗传学和心理学上都有研究并获得了博士学位。精神病遗传学我的博士这项工作是基于这样的原则，即气质和神经认知功能可以用作中间特征或内在表型，以便于鉴定易患bipola障碍的遗传变异。随后，我在NIMH的Drevets博士的指导下完成了博士后研究，在那里我专注于PET和MRI，以期利用这些技术进行遗传分析。我目前是桂冠脑研究所（LIBR）的助理教授，专注于弥合重度抑郁症（MDD）中免疫功能障碍和神经影像异常之间的差距。假设炎症通过改变色氨酸（TRP）（血清素的前体）的分解、降低血清素水平和增加犬尿氨酸（KYN）和神经毒性KYN代谢物（如3-羟基犬尿氨酸（3 HK）和喹啉酸（QUIN））的合成而促成抑郁症。驱动这种代谢分流朝向KYN合成的促炎细胞因子之一是白细胞介素6（IL 6），其作用部分地被抗炎细胞因子白细胞介素10（IL 10）抵消。我提出的K 01的目的是检查IL 6、IL 10、TRP/KYN代谢物的血浆浓度与MDD的三种神经生理学相关性之间的关联：（a）杏仁核、海马体和膝周前扣带对情绪化面孔的血液动力学反应的异常模式，（B）海马体体积的减少，和（c）膝周前扣带皮层（ACC）的体积和/或厚度的减小。采用其他常用测量细胞因子的事后分析：IN？，还将进行IL 2、IL 4、IL 5、IL 1、IL 8、TNF和IL 12 p70（以下称为微珠阵列：BA细胞因子）。还将事后评估杏仁核体积的减少。将招募60名MDD患者和60名健康对照（HC）。将使用细胞因子微珠阵列测量IL 6、IL 10和BA细胞因子的血浆浓度，而TRP、KYN和3 HK的测量将使用高效液相色谱法（HPLC）获得。将在配备32通道线圈的GE MR 750 3 T扫描仪上进行成像。将功能图像（体素尺寸=2.5mm x 2.5mm x 2.9mm）与解剖图像（体素尺寸=0.86mm x 0.86mm x 0.9mm）配准，进而用于获得FreeSurfer衍生的体积和皮质厚度测量值。此外，高分辨率T1和T2图像（0.47mm x 0.47mm x 2.0mm）将用于杏仁核和海马和ACC的子区域的手动分割。在6对匹配的MDD患者和HC中获得的试验数据支持我们的几个假设：（a）。与HC相比，MDD患者的海马较小，ACC较薄，并且在对遮盖的悲伤面孔和快乐面孔的反应中表现出更大的杏仁核、海马和腹内侧PFC活性。（B）。MDD患者IL 6和3 HK水平高于HC，而IL 10水平低于HC。（c）.较高浓度的IL 6与较低的海马和杏仁核体积，以及更大的左膝周ACC反应掩盖悲伤与快乐的面孔。相反，IL 10浓度与海马体积和ACC厚度呈正相关。（d）.较高水平的3-HK与杏仁核体积和ACC厚度的减少有关，并且对掩蔽的悲伤面孔和快乐面孔的右侧海马反应更大。（e）. TRP-KYN比率与右杏仁核对悲伤和快乐面孔的反应降低呈负相关。该项目可能是阐明情绪障碍的病理生理机制之一的初步步骤，可能有助于开发针对该途径的下一代抗抑郁药物，以及用于识别MDD“炎症”亚型患者的非侵入性免疫学生物标志物。这个K 01应用程序旨在为我提供在神经免疫学和神经影像学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，即为情绪障碍的免疫学基础提供知识见解，从而促进新疗法的发展。（一）.我将发展免疫功能的工作知识，并了解细胞因子和TRP-KYN代谢对中枢神经系统神经炎症过程的影响。该培训将在Dantzer博士和蒂格博士的指导下进行，并将分别访问两个实验室以学习HPLC和细胞因子阵列技术。（B）。在Bellgowan和Drevets博士的指导下，我将精通功能磁共振成像技术和数据分析。Bellgowan博士的“动手”工作将侧重于使用AFNI的实验设计和数据处理，而Drevets博士将强调文献背景下出现的方法学问题。此外，我将参加AFNI的“训练营”和FreeSurfer培训课程，分别在我的培训的第2年和第3年。(c)在Dr. Drevets的指导下，我将加深对情绪障碍的神经生物学的了解，并将获得神经解剖学的进一步培训，使我能够更好地解释文献中报道的成像结果，并促进海马和ACC亚区的手动分割。(d)我将获得进一步的研究道德培训，并发展重要的“软技能”，如冲突管理，招聘，监督和指导工作人员和学生。