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（由适用提供）：我毕业于学士学位在遗传学和心理学中，并获得了博士学位。在精神遗传学中。我的博士学位工作基于这样的原则，即温度和神经认知功能可以用作中间性状或内型型，以促进易于鉴定bipola疾病的遗传变异。随后，我在NIMH博士Drevets博士博士博士博士Drevets博士的心态下完成了博士后奖学金，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，重点是弥合主要抑郁症（MDD）免疫功能障碍与神经影像异常之间的差距。假设炎症是通过改变色氨酸（TRP）的分解，羟色胺的前体，降低5-羟色胺水平并增加了雌激素（Kyn）（Kyn）（Kyn）和神经毒性的Kyn kyn kyn代谢物的合成，从而导致抑郁症。将这种代谢分流向Kyn合成的促炎细胞因子之一是白介素6（IL6），这种作用由抗炎细胞因子（ILLEUIN 10（IL10））部分抵消。 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, （c）降低前扣带回皮层的体积和/或厚度（ACC）。与其他常见的细胞因子进行的事后分析：in？,, IL2，IL4，IL5，IL1€，IL8，TNF¿和IL12P70（以下称珠阵列：BA细胞因子）也将进行。杏仁核体积减少也将在事后评估。将招募60例MDD患者和60名健康对照（HCS）。 IL6，IL10和BA细胞因子的血浆浓度将使用细胞因子珠阵列进行测量，而使用高性能液相色谱（HPLC），将获得TRP，KYN和3HK的测量值。成像将在GE MR750 3T扫描仪上进行32通道线圈。功能图像（体素尺寸= 2.5mm x 2.5mm x 2.9mm）将被核检查到解剖图像（体素尺寸= 0.86mm x 0.86mm x 0.9mm x 0.9mm），依次将用于获得自由式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和ACC的子区域。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）。 MDD患者的海马较小，较薄的ACC，并且表现出比HCS比HCS更大的杏仁核，海马和腹侧PFC活性。 （b）。 MDD患者的IL6和3HK水平更高，但IL10水平低于HC。 （c）。较高浓度的IL6与较低的海马和杏仁核体积有关，以及对蒙面的SAD与快乐面孔的左左阴性ACC反应更大。相反，IL10浓度似乎与海马体积和ACC厚度正相关。 （d）。较高的3-HK水平与减少杏仁核的体积和ACC厚度相关，以及对蒙面的SAD与快乐面孔的右海马反应更大。 （e）。 TRP-KYN比率与右杏仁核对SAD与快乐面孔的反应降低相关。该项目可能构成阐明情绪障碍的病理生理机制之一的初步步骤，可能支持针对该途径的下一代抗抑郁药的发展，以及用于识别MDD炎症性的患者的非侵入性免疫生物标志物。该K01应用程序旨在为我提供在神经免疫学和神经成像领域的界面上工作所需的培训，从而使我能够实现我的长期职业目标，以提供对情绪障碍的免疫学基础的智力洞察力，从而促进新型治疗的发展。 （一个）。我将发展有关免疫功能的工作知识，并了解细胞因子和TRP-KYN代谢对CNS神经炎症过程的影响。该培训将在Drs的心态下进行。 Dantzer和Teague，并将分别对两个实验室进行访问，分别学习HPLC和细胞因子阵列技术。 （b）。在DR的心态下，我将熟练精通fMRI技术和数据分析。贝尔戈万和德雷仪。与Bellgowan博士的“动手”合作将专注于使用AFNI的实验设计和数据处理，而Drevets博士将强调在文献背景下引起的方法论问题。此外，我将分别参加我培训的2年级和第3年的AFNI“ Bootcamp”和FreeSurfer培训课程。 （c）在Drvets博士的心态下，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支持海马和ACC子区域的手动细分。 （d）我将获得进一步的研究伦理培训，并发展重要的“柔和技能”，例如冲突管理以及员工和学生的招聘，监督和心理。