CTBI: Traumatic brain injury-induced inflammation effects on cognitive evaluations and response inhibition: Mechanisms of increased risk forsuicidality

CTBI：创伤性脑损伤诱发的炎症对认知评估和反应抑制的影响：自杀风险增加的机制

• 批准号: 10662374
• 负责人: Marianne Goodman
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662374
• 关键词: Address; Amygdaloid structure; Animals; Anisotropy; Anterior; Award; Behavior; Behavior assessment; Behavioral; Biological Markers; Blood; Brain; Caring; Clinical assessments; Cognitive; Complement; Data; Death Rate; Decision Making; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Evaluation; Exhibits; Feeling suicidal; Female; Freedom; Functional Magnetic Resonance Imaging; Functional disorder; Genetic study; Human; Impairment; Impulsive Behavior; Impulsivity; Individual; Inferior; Inflammation; MRI Scans; Machine Learning; Magnetic Resonance Imaging; Major Depressive Disorder; Matched Group; Measures; Modeling; Motor; Neurobiology; Neurons; New Jersey; Performance; Post-Traumatic Stress Disorders; Psychometrics; Rattus; Recording of previous events; Research; Risk; Risk Factors; Role; Serotonergic System; Site; Stress; Suicide; Suicide attempt; Temporal Lobe; Traumatic Brain Injury; Veterans; animal data; biomarker identification; causal model; cingulate gyrus; comorbidity; design; discounting; emotion regulation; frontal lobe; frontal lobe function; genomic biomarker; human data; human imaging; male; mild traumatic brain injury; military veteran; multimodality; neural circuit; neural correlate; neuroimaging; neuroinflammation; neuronal circuitry; novel strategies; operation; predictive marker; response; suicidal; suicidal behavior; suicidal morbidity; suicidal risk; suicide rate; trait; translational approach; white matter

This Merit proposal is part of a BLR&D Collaborative Merit Award for TBI (CTBI) proposal (RFP #BX-19- 006) involving three separate but integrated proposals that together investigate the mechanisms by which TBI enhances impulsivity and suicidal behavior in Veterans. The rationale for the collaborative project is to combine neurobiological mechanistic studies in animals with human imaging and biomarker analysis to understand the manner in which TBI influences impulsivity and suicidal behavior. The overarching hypothesis is that TBI enhances impulsivity, a risk factor for suicide particularly in response to stress, through inflammation and dysfunction of the serotonin system and frontal lobe circuitry. Recent research increasingly highlights mild traumatic brain injury (mTBI) as a risk factor for suicidal thoughts and behaviors, including death by suicide. A study by Co-I Brenner found that Veterans with mTBI died by suicide at 1.8 the rate of the general Veteran population. The elevated suicide risk in Veterans with TBI is also consistent with previous research in civilians. Nevertheless, the study of suicide among those with mTBI is limited and there exists minimal understanding of the mechanism underlying this enhanced suicide risk in mTBI. There is a growing appreciation of the role of dysfunction in the circuits and white matter tracts underlying decision making in individuals with mTBI and history of a suicide attempt. However, neuroimaging studies examining the intersection of suicidal behavior and mTBI are limited. Moreover, how impulsivity and mTBI influences the development of suicidal behavior is also unclear. This project aims to address this gap with a neuroimaging project examining facets of impulsivity in Veterans with mTBI and a suicide attempt history. The James J. Peters VA (JJPVA) site proposes to investigate in male and female OEF/OIF/OND Veterans (n=140), the relationship of cognitive and behavioral impulsivity using a 2 (mTBI+/-) x 2 (history of suicide attempt (SA)+/-) design approach. Specifically, we will be examining four groups of Veterans: mTBI+/ SA+, mTBI+/SA-, mTBI-/SA+ and mTBI-/SA-. This project complements the animal studies being conducted at the New Jersey VA site by utilizing the same paradigms in humans during fMRI: the Go/No-go (motor) and Delay discounting (cognitive) task to assess impulsivity in both animals and humans. A primary objective of this study is to characterize alterations in brain activity and functional connectivity related to motor and cognitive impulsivity during fMRI in our four groups of Veterans. The secondary objective is to examine the relationship between white matter integrity using diffusion tensor imaging (DTI), and dynamic causal modeling with data from our two behavioral tasks of impulsivity performed during fMRI, along with psychometrically-validated measures of impulsivity. The third objective will be to determine similarities and differences in impulsivity data from animal TBI models and humans. All Veterans will receive rigorous diagnostic assessments, measures of impulsivity, clinical assessments of suicidal behavior, and a MRI scan (including structural MRI, DTI, and fMRI while performing impulsivity tasks). Blood will also be obtained for biomarker analysis, conducted by the Indianapolis VA site. Identifying potential neurobiological biomarkers for heightened suicide risk in Veterans with mTBI is essential for developing targeted care. The proposed research is translational as similar parallel analyses will be performed in humans and animals for investigating common neuronal circuits activated by impulsivity and genomic biomarkers.

该优异提案是 BLR&D TBI (CTBI) 提案协作优异奖的一部分 (RFP #BX-19- 006）涉及三个独立但综​​合的提案，共同研究 TBI 的机制 增强退伍军人的冲动和自杀行为。该合作项目的基本原理是将 通过人体成像和生物标志物分析对动物进行神经生物学机制研究，以了解 TBI 影响冲动和自杀行为的方式。总体假设是 TBI 通过炎症和压力增强冲动，这是自杀的危险因素，特别是在应对压力时 血清素系统和额叶电路功能障碍。 最近的研究越来越强调轻度创伤性脑损伤（mTBI）是自杀的危险因素 思想和行为，包括自杀死亡。布伦纳 (Co-I Brenner) 的一项研究发现，患有 mTBI 的退伍军人 自杀率是退伍军人总人口的 1.8 倍。患有 TBI 的退伍军人自杀风险升高 也与之前针对平民的研究结果一致。尽管如此，关于 mTBI 患者自杀的研究 的认识有限，而且对自杀风险增加背后的机制了解甚少。 mTBI。人们越来越认识到回路和白质束功能障碍的作用 患有 mTBI 且有自杀企图史的个体的基本决策。然而，神经影像学 探讨自杀行为与 mTBI 交叉点的研究有限。此外，冲动和 mTBI 对自杀行为发展的影响尚不清楚。该项目旨在解决这一差距 通过一个神经影像项目检查患有 mTBI 和自杀未遂的退伍军人的冲动方面 历史。 James J. Peters VA (JJPVA) 网站提议对男性和女性 OEF/OIF/OND 退伍军人进行调查 (n=140)，认知和行为冲动的关系使用 2 (mTBI+/-) x 2（自杀史） 尝试（SA）+/-）设计方法。具体来说，我们将检查四组退伍军人：mTBI+/SA+、 mTBI+/SA-、mTBI-/SA+ 和 mTBI-/SA-。该项目补充了正在进行的动物研究 新泽西州 VA 网站在功能磁共振成像期间利用与人类相同的范例：Go/No-go（电机）和延迟 贴现（认知）任务来评估动物和人类的冲动。本研究的主要目标 旨在表征与运动和认知相关的大脑活动和功能连接的变化 我们四组退伍军人在功能磁共振成像期间的冲动。次要目标是检查关系 使用扩散张量成像 (DTI) 的白质完整性与数据动态因果建模之间的关系 来自我们在功能磁共振成像期间执行的两项冲动行为任务，以及经过心理测量验证的 冲动的衡量标准。第三个目标是确定冲动数据的异同 来自动物 TBI 模型和人类。所有退伍军人都将接受严格的诊断评估、措施 冲动、自杀行为的临床评估以及 MRI 扫描（包括结构 MRI、DTI 和 fMRI） 在执行冲动任务时）。还将采集血液用于生物标志物分析，由 弗吉尼亚州印第安纳波利斯网站。识别退伍军人自杀风险增加的潜在神经生物学生物标志物 mTBI 对于开展有针对性的护理至关重要。拟议的研究可转化为类似的平行研究 将在人类和动物中进行分析，以研究由以下物质激活的常见神经元回路 冲动和基因组生物标志物。