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

本建议书是BLR&D TBI(CTBI)建议书(RFP#BX-19- 006)涉及三个独立但综合的提案，这些提案共同调查全面预算执行的机制 增强退伍军人的冲动和自杀行为。协作项目的基本原理是将 通过对动物神经生物学机制的研究，结合人体成像和生物标志物分析来了解 脑外伤影响冲动和自杀行为的方式。最重要的假设是，TBI 增强冲动，这是自杀的一个危险因素，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，包括自杀死亡。Co-I Brenner的一项研究发现，患有mTBI的退伍军人 自杀率为普通退伍军人的1.8%。退伍军人合并脑外伤后自杀风险升高 这也与之前在平民中进行的研究一致。尽管如此，关于轻度颅脑损伤患者自杀的研究 是有限的，而且对这种增加的自杀风险背后的机制还存在很少的了解 MTBI。对环路和白质束功能障碍的认识越来越多。 患有mTBI和自杀未遂史的个体的潜在决策。然而，神经成像 研究自杀行为和mTBI的交叉点的研究有限。此外，冲动和冲动 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 一个神经成像项目研究了患有mTBI和自杀未遂的退伍军人的冲动方面 历史。 詹姆斯·J·彼得斯VA(JJPVA)网站建议对男性和女性OEF/OIF/OND退伍军人进行调查 (n=140)，使用2(mTBI+/-)x 2(自杀史)的认知和行为冲动的关系 尝试(SA)+/-)设计方法。具体地说，我们将检查四组退伍军人：MTBI+/SA+， MTBI+/SA-、mTBI-/SA+和mTBI-/SA-。该项目是对正在进行的动物研究的补充 新泽西州VA站点在功能磁共振成像中使用了与人类相同的范式：进行/不进行(运动)和延迟 对(认知)任务进行折扣，以评估动物和人类的冲动。这项研究的主要目的之一 是描述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中的冲动。次要目标是检查两者之间的关系 使用扩散张量成像(DTI)的白质完整性与使用数据的动态因果模型之间的关系 从我们在功能磁共振成像中执行的两个冲动行为任务，以及心理测量学验证 冲动的衡量标准。第三个目标是确定冲动数据的相似性和差异性 来自动物脑损伤模型和人类。所有退伍军人都将接受严格的诊断评估，测量 冲动、自杀行为的临床评估和MRI扫描(包括结构MRI、DTI和fMRI 同时执行冲动任务)。血液也将被采集进行生物标志物分析，由 印第安纳波利斯退伍军人事务部。确定退伍军人自杀风险增加的潜在神经生物学标志物 使用mTBI对于发展有针对性的护理是必不可少的。建议的研究是翻译为类似的平行 将在人类和动物身上进行分析，以研究由 冲动和基因组生物标记物。

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.