The Interaction of Stress and Mild Traumatic Brain Injury

压力与轻度创伤性脑损伤的相互作用

• 批准号: 9883869
• 负责人: COLEEN M. ATKINS
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9883869
• 关键词: Acoustics; Address; Adult; Affect; Afghanistan; Age-Months; Anxiety; Atrophic; Brain Concussion; Child; Childhood; Chronic; Clinical; Clinical Trials; Cognitive; Cognitive deficits; Corticosterone; Cues; Data; Dementia; Development; Drug usage; Early Intervention; Emotional; Environment; Event; Exhibits; Exposure to; Female; Frequencies; Glucocorticoid Receptor; Glucocorticoids; Gulf War; Headache; Health; Hippocampus (Brain); Hydrocortisone; Hyperactive behavior; Impaired cognition; Impairment; Injury; Intervention; Iraq; Learning; Left; Life Experience; Link; Measures; Medical; Memory; Memory impairment; Mental Depression; Mifepristone; Military Personnel; Mineralocorticoid Receptor; Modeling; Neurologic; Neurons; Operative Surgical Procedures; Outcome; Pathology; Patients; Pharmaceutical Preparations; Phase; Predisposing Factor; Protocols documentation; Rattus; Recovery; Reflex action; Rehabilitation therapy; Reporting; Risk; Risk Factors; Screening Result; Series; Short-Term Memory; Sleep; Soldier; Spironolactone; Sprague-Dawley Rats; Stress; Sucrose; Symptoms; Testing; Therapeutic; Training; Traumatic Brain Injury; United States; Verbal Learning; Veterans; base; behavior test; biological adaptation to stress; cognitive rehabilitation; cognitive training; cohort; combinatorial; conditioned fear; corticosterone receptor; depressive symptoms; early life stress; early screening; experience; fluid percussion injury; glucocorticoid receptor alpha; hypothalamic-pituitary-adrenal axis; improved; improved outcome; male; maltreated children; maltreatment; maternal separation; memory retrieval; middle age; mild traumatic brain injury; neglect; persistent symptom; postnatal; preference; pup; rehabilitation paradigm; response; restraint stress; service member; sham surgery; water maze; young adult

[Mild traumatic brain injury (mTBI) is a major clinical problem in United States Veterans and reported by 315,897 service members since 2000, representing 82.3% of all TBIs reported in military personnel. Although the majority of people with mTBI recover within a few weeks, 25% of military personnel with mTBI have persistent symptoms lasting for at least 3 months post-injury.] However, the factors that contribute to developing persistent symptoms after mTBI are unknown. Understanding the risk factors involved in the persistent sequelae after mTBI could provide clinicians with the ability to identify Veterans at risk and enable early interventions. One potential factor recently identified in a study of mTBI patients is pre-exposure to stressful life experiences. Chronic early life stress is highly prevalent in the United States, and a major cause of early life stress in childhood is neglect. Maltreated children are at risk for developing long-term emotional, cognitive and medical problems that emerge during middle age. One potential mechanism linking early life stress to neurological problems in adulthood is hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Early life stress results in a heightened and prolonged cortisol response in response to stress encountered in adulthood. Using brief daily maternal separation in rat pups to model childhood neglect, we have found that the combination of early life stress with mTBI in adulthood impaired hippocampal-dependent learning and increased corticosterone levels in response to restraint stress. Based on these preliminary data, the main hypothesis of this proposal is to determine if early life stress prior to mTBI is a risk factor for persistent memory problems after mTBI and if these memory impairments can be improved with cognitive rehabilitation in combination with a glucocorticoid receptor antagonist. To test this hypothesis, the following aims are proposed: 1) To determine if early life stress prior to mTBI results in persistent memory impairments and 2) To determine if early life stress prior to mTBI potentiates the response to stress in adulthood and if a glucocorticoid receptor antagonist in combination with cognitive training improves memory deficits. These studies will address a highly significant clinical question, do predisposing factors contribute to the development of persistent neurological sequela after mTBI? We will determine if an early life stress event prior to mTBI exacerbates memory impairments and test whether implicit cognitive training in combination with a clinically approved drug, mifepristone, can mitigate the effects of early life stress on mTBI outcome during cognitive rehabilitation. [This proposal may improve Veteran health by providing scientific support for screening for early life stress in Veterans who have had a mTBI and use these screening results to indicate whether this combinatorial treatment may be potentially efficacious in Veterans.]

[轻度创伤性脑损伤 (mTBI) 是美国退伍军人的一个主要临床问题，有 315,897 人报告 自 2000 年以来，军人中发生过 TBI，占军事人员中报告的所有 TBI 的 82.3%。虽然大多数 的 mTBI 患者在几周内康复，25% 的 mTBI 军事人员有持续症状 受伤后持续至少 3 个月。] 然而，导致持续症状的因素 mTBI 后的情况尚不清楚。了解 mTBI 后持续性后遗症所涉及的危险因素可以 使临床医生能够识别处于危险中的退伍军人并进行早期干预。一个潜在因素 最近在一项针对 mTBI 患者的研究中发现，这些患者的症状是预先暴露于压力性的生活经历。慢性早年生活 压力在美国非常普遍，而童年早期生活压力的一个主要原因是忽视。 受虐待的儿童面临出现长期情感、认知和医疗问题的风险 中年时期。将早期生活压力与成年神经系统问题联系起来的一种潜在机制是 下丘脑-垂体-肾上腺（HPA）轴过度活跃。早期生活压力会导致 延长皮质醇反应以应对成年期遇到的压力。使用简短的日常产妇 通过对幼鼠的分离来模拟童年忽视，我们发现早期生活压力与 成年期 mTBI 损害海马依赖性学习，并导致皮质酮水平升高 以抑制压力。基于这些初步数据，该提案的主要假设是确定是否尽早 mTBI 之前的生活压力是 mTBI 后持续性记忆问题的危险因素，如果这些记忆 认知康复与糖皮质激素受体相结合可以改善损伤 对手。为了检验这一假设，提出了以下目标：1）确定早期生活压力是否在 mTBI 会导致持续性记忆障碍，并且 2) 确定 mTBI 之前的早期生活压力是否会增强 成年期对压力的反应以及糖皮质激素受体拮抗剂与认知功能相结合的情况 训练可以改善记忆缺陷。这些研究将解决一个非常重要的临床问题， 易感因素导致 mTBI 后持续性神经系统后遗症的发生？我们将 确定 mTBI 之前的早期生活压力事件是否会加剧记忆障碍，并测试是否内隐 认知训练与临床批准的药物米非司酮相结合，可以减轻早期认知障碍的影响。 认知康复期间生活压力对 mTBI 结果的影响。 [该提案可以通过以下方式改善退伍军人的健康 为患有 mTBI 的退伍军人筛查早期生活压力提供科学支持，并使用这些 筛选结果表明这种组合治疗是否对退伍军人可能有效。]