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: 10425246
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425246
• 关键词: Address; Amygdaloid structure; Animals; Anisotropy; Anterior; Award; 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; Time; Traumatic Brain Injury; Veterans; animal data; base; causal model; cingulate gyrus; cognitive task; comorbidity; design; discounting; emotion regulation; frontal lobe; frontal lobe function; genomic biomarker; human data; human imaging; imaging biomarker; male; mild traumatic brain injury; military veteran; motor behavior; 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.

本优秀提案是BLR&D合作优秀奖TBI（CTBI）提案的一部分（RFP #BX-19- 006)涉及三个独立但综合的建议，共同研究TBI的机制， 增强了退伍军人的冲动和自杀行为。合作项目的基本原理是将联合收割机 在动物中进行神经生物学机制研究，并进行人体成像和生物标志物分析，以了解 TBI影响冲动和自杀行为的方式。总体假设是， 增强冲动，这是自杀的风险因素，特别是在应对压力时，通过炎症和 5-羟色胺系统和额叶回路功能障碍。 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。Co-I Brenner的一项研究发现， 自杀率是一般退伍军人的1.8倍。TBI退伍军人的自杀风险增加 这也与之前在平民中的研究一致。然而，对mTBI患者自杀的研究 是有限的，而且对这种自杀风险增加的机制了解甚少， mTBI。越来越多的人认识到功能障碍在回路和白色物质束中的作用 mTBI患者和自杀未遂史的潜在决策。然而，神经成像 研究自杀行为和mTBI的交叉点是有限的。此外，冲动和 mTBI对自杀行为发展的影响也不清楚。该项目旨在解决这一差距 一个神经成像项目检查了患有mTBI和自杀企图的退伍军人的冲动方面 历史 James J. Peters VA（JJPVA）研究中心建议在男性和女性OEF/OIF/OND退伍军人中进行研究 （n=140），认知和行为冲动的关系，使用2（mTBI+/-）× 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VA站点通过在fMRI期间利用人类相同的范例：Go/No-go（运动）和延迟 贴现（认知）任务，以评估动物和人类的冲动。本研究的主要目的是 是描述大脑活动和与运动和认知相关的功能连接的变化， 在我们的四组退伍军人中进行了功能性磁共振成像。第二个目标是检查 使用扩散张量成像（DTI）的白色物质完整性与数据的动态因果建模之间的关系 从我们在功能磁共振成像中进行的两个冲动行为任务，沿着心理测量学验证的 衡量冲动的标准第三个目标是确定冲动性数据的相似性和差异性 从动物TBI模型和人类。所有退伍军人将接受严格的诊断评估， 冲动性、自杀行为的临床评估和MRI扫描（包括结构MRI、DTI和fMRI 当执行冲动性任务时）。还将获得血液用于生物标志物分析，由 印第安纳波利斯VA站点。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对于发展有针对性的护理至关重要。拟议的研究是翻译作为类似的平行 将在人类和动物中进行分析，以研究由 冲动和基因生物标记物。