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: 8717731
• 负责人: Jonathan Savitz
• 金额: $ 18.08万
• 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/8717731
• 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-1; 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）：我获得了遗传学和心理学学士学位，并获得了精神病遗传学博士学位。我的博士学位工作基于气质和神经认知功能可以作为中间特征的原则。随后，我在 NIMH 的 Drevets 博士的指导下完成了博士后研究。我目前是获奖者大脑研究所 (LIBR) 的助理教授，致力于弥合重度抑郁症 (MDD) 中免疫功能障碍和神经影像异常之间的差距。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的合成而导致抑郁症(KYN) 和神经毒性 KYN 代谢物，例如 3-羟基犬尿氨酸 (3HK) 和喹啉酸 (QUIN)，驱动这种代谢分流至 KYN 合成的促炎细胞因子之一是白细胞介素 6 (IL6)，这种作用是我提出的 K01 的目的是检查血浆浓度之间的关联。 IL6、IL10、TRP/KYN 代谢物和 MDD 的三个神经生理学相关因素：(a) 杏仁核、海马和膝部 ACC 对情绪化面孔的血流动力学反应异常模式，(b) 海马体积减少，以及 ( c) 膝前扣带皮层 (ACC) 的体积和/或厚度减少 使用额外的、常用测量的细胞因子进行事后分析： IN?、IL2、IL4、IL5、IL1¿ , IL8, TNF¿和 IL12p70（以下为珠阵列：BA 细胞因子）还将招募 60 名 MDD 患者和 60 名健康对照 (HC) 的血浆浓度。和 BA 细胞因子将使用细胞因子珠阵列进行测量，而 TRP、KYN 和 3HK 的测量将通过高效液相色谱法获得(HPLC) 将在具有 32 通道线圈的 GE MR750 3T 扫描仪上进行，功能图像（体素尺寸 = 2.5 毫米 x 2.5 毫米 x 2.9 毫米）将与解剖图像（体素尺寸 = 0.86 毫米 x 2.9 毫米）进行配准。 0.86 毫米 x 0.9 毫米），这将用于获得 FreeSurfer 衍生的体积和皮质厚度测量。此外，高分辨率 T1 和 T2 图像 (0.47mm x 0.47mm x 2.0mm) 将用于手动分割杏仁核和海马体亚区域，并在 6 对匹配的 MDD 患者和 HC 中获得试点数据。我们的假设：(a) MDD 患者的海马体较小，ACC 较薄，并且杏仁核、海马体和大脑皮质较大。与 HC 相比，MDD 患者的腹内侧前额叶皮层 (PFC) 活性较高，但 IL10 水平较低 (c)。杏仁核体积，以及线下蒙面悲伤和快乐面孔的左膝周围 ACC 反应更大，IL10 浓度似乎与海马体积和 ACC 厚度呈正相关。 (d) 较高水平的 3-HK 与杏仁核体积和 ACC 厚度减少有关，并且右侧海马对隐藏的悲伤和快乐面孔的反应较大 (e)。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，有可能促进针对这一途径的下一代抗抑郁药物的开发，例如以及用于识别 MDD“炎症”亚型患者的非侵入性免疫生物标记物。此 K01 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，从而使我能够实现长期目标。长期职业目标是提供对情绪障碍的免疫学基础的深入了解，从而促进新疗法的开发 (a)。进程在该培训将在 Dantzer 和 Teague 博士的指导下进行，并将分别参观两个实验室，以学习 HPLC 和细胞因子阵列技术 (b)。 Bellgowan 博士和 Drevets 的“实践”工作将侧重于使用 AFNI 进行实验设计和数据处理，而 Drevets 则将强调导师背景下出现的方法学问题。此外，我将在培训的第二年和第三年分别参加 AFNI“训练营”和 FreeSurfer 培训课程 (c) 在 Drevets 的指导下，我将加深对情绪障碍神经生物学的了解。并将获得神经解剖学方面的进一步培训，使我能够更好地解释文献中报告的成像结果，并促进海马和 ACC 分区的手动分割 (d) 我将获得研究伦理方面的进一步培训并发展重要的知识。 “软技能”，例如冲突管理以及员工和学生的招聘、监督和指导。