Sex differences in traumatic brain injury: Neural circuit mediators of overlapping stress and physical effects

创伤性脑损伤的性别差异：重叠压力和物理效应的神经回路调节因素

基本信息

批准号：
10751089
负责人：
Megan E Huibregtse
金额：
$ 7.61万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-14 至 2025-07-13
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10751089
关键词：
Accident and Emergency department Acute Address Affect American Animals Antiinflammatory Effect Astrocytes Attention Award Axon Biometry Blood specimen Brain Brain Concussion Brain Injuries Chronic Post Traumatic Stress Disorder Chronic stress Complex Congresses Consensus Craniocerebral Trauma DSM-V Data Data Reporting Data Science Data Set Diagnosis Diffusion Magnetic Resonance Imaging Dimensions Discipline Estradiol Exhibits Extinction Female Fright Functional Magnetic Resonance Imaging Functional disorder Glial Fibrillary Acidic Protein Goals Head Headache Health Surveys Hormonal Hormones Hour Human Impairment Individual Injury Intermediate Filament Proteins Intervention Investigation Knowledge Life Light Literature Longitudinal Studies Masks Measures Mechanics Mediating Mediator Menstrual cycle Mental Depression Mental Health Mentors Military Personnel Neurobiology Neuroendocrinology Neurosciences Research Outcome Participant Patient Recruitments Patient Self-Report Patients Perimenopause Persons Physical Medicine Population Post-Traumatic Stress Disorders Predisposition Prevalence Psychopathology Qualifying Quality of life Questionnaires Reporting Research Research Personnel Rest Risk Risk Factors Role Sampling Sex Differences Signs and Symptoms Site Sports Stress Symptoms TBI Patients Time Training Trauma Traumatic Brain Injury United States Vehicle crash Visual Woman acute stress associated symptom biological adaptation to stress career cohort decrease resilience depressive symptoms experience falls female sex hormone health disparity health related quality of life intimate partner violence male medical attention member men mental state mild traumatic brain injury neural circuit neural correlate neuroimaging neuroimaging marker neuroprotection neuropsychiatry neurosteroids new therapeutic target novel physical assault post-doctoral training post-trauma pre-clinical research psychosocial stressors recruit reproductive response sex sexual assault tool trauma exposure traumatic event violence against women white matter

项目摘要

PROJECT SUMMARY Women experience worse symptoms and outcomes following traumatic brain injury (TBI), contrary to the consensus in preclinical research that female sex hormones confer neuroprotection. Multiple mechanisms have been proposed to drive this health disparity, including hormonal fluctuations during the menstrual cycle and into the menopausal transition, a predisposition to seek medical attention or report symptoms, and increased neurobiological vulnerability to injury. In particular, increased vulnerability to mechanical trauma in female axons and the role of neurosteroid hormones have not been thoroughly examined in human TBI. While mild traumatic brain injuries (mTBI) make up the majority of TBIs, research often focuses on a specific sub-type of mTBI: sports-related concussions. However, many people experience head trauma during a traumatic event, such as motor vehicle collisions, physical assault, sexual assault, or falls, and the lifetime prevalence of experiencing at least traumatic event is extremely high (90%). As the literature on sports-related concussions may not always generalize to this trauma-exposed population, we aim to characterize sex differences in structural and functional connectivity (Aim 1), examine sex-dependent associations between TBI pathophysiology and outcomes (Aim 2), and finally assess the influence of concurrent estradiol levels on TBI outcomes and neuroimaging markers (Aim 3) To address these aims, I will leverage a large, existing dataset from the AURORA study, a multisite, longitudinal study of posttraumatic outcomes. Participants were recruited to AURORA if they presented to a participating Emergency Department (ED) within 72 hours of a qualifying traumatic event and then were followed through 12-months posttrauma. Participants were assessed using a multidimensional range of tools and measures to general a one-of-a-kind, rich dataset to study the complex, co-occurring symptoms and overlapping neural correlates of adverse posttraumatic neuropsychiatric sequelae across a variety of disciplines. About one-third of AURORA participants met modified American Congress of Rehabilitation Medicine criteria for TBI. However, as the acute and chronic stress responses can mask and compound signs and symptoms of TBI, it is essential to use an objective marker to establish TBI in this trauma- exposed cohort. We propose to use ED GFAP levels to identify individuals with TBI, which have shown to be significantly elevated in individuals with TBI for several days following presentation at the ED. TBI outcomes will include not only somatic symptoms (e.g., headache, sensitivity to light) but also PTSD and depression symptoms and mental health-related quality of life. Completion of this project will not only inform our understanding of neurobiological factors that affect sex differences in TBI outcomes but also provide excellent postdoctoral training for the applicant in diffusion magnetic resonance imaging, resting-state functional connectivity, neuroendocrinology, PTSD and stress-related psychopathology, and biostatistics and data science for human neuroscience research, preparing her for a successful career as an independent scholar.

项目概要女性在遭受创伤性脑损伤 (TBI) 后会出现更严重的症状和结果，这与临床前研究一致认为女性性激素具有神经保护作用。多重机制有人提议推动这种健康差异，包括月经周期期间的荷尔蒙波动进入更年期过渡期，倾向于寻求医疗救助或报告症状，以及神经生物学对损伤的脆弱性增加。特别是，机械创伤的脆弱性增加女性轴突和神经类固醇激素的作用尚未在人类 TBI 中得到彻底研究。虽然轻度创伤性脑损伤 (mTBI) 占 TBI 的大多数，但研究通常侧重于特定的 mTBI 的亚型：运动相关脑震荡。然而，许多人在手术过程中都会经历头部外伤。创伤事件，例如机动车碰撞、人身攻击、性侵犯或跌倒，以及生命周期至少经历过创伤性事件的发生率极高（90%）。正如体育相关文献脑震荡可能并不总是普遍适用于这些遭受创伤的人群，我们的目标是描述性别特征结构和功能连接的差异（目标 1），检查 TBI 之间的性别依赖性关联病理生理学和结果（目标 2），最后评估同时雌二醇水平对 TBI 的影响结果和神经影像标记（目标 3）为了实现这些目标，我将利用大型现有数据集来自 AURORA 研究，这是一项针对创伤后结果的多中心纵向研究。参与者已招募如果他们在符合条件的 72 小时内向参与的急诊科 (ED) 报告，则向 AURORA 报告创伤事件，然后进行创伤后 12 个月的随访。使用以下方法对参与者进行评估：多维的工具和措施，以通用一个独一无二的、丰富的数据集来研究复杂的、不良创伤后神经精神后遗症的并发症状和重叠神经相关性跨越多个学科。大约三分之一的 AURORA 参与者会见了修改后的美国国会 TBI 的康复医学标准。然而，由于急性和慢性应激反应可以掩盖和由于 TBI 的症状和体征复合，因此有必要使用客观标记来确定这种创伤中的 TBI 暴露队列。我们建议使用 ED GFAP 水平来识别患有 TBI 的个体，这已被证明是患有 TBI 的患者在急诊室就诊后的几天内显着升高。创伤性脑损伤的结果不仅包括躯体症状（例如头痛、对光敏感），还包括创伤后应激障碍（PTSD）和抑郁症症状和心理健康相关的生活质量。该项目的完成不仅将告知我们了解影响 TBI 结果性别差异的神经生物学因素，但也提供了良好的为申请人提供扩散磁共振成像、静息态功能的博士后培训连接性、神经内分泌学、创伤后应激障碍和压力相关的精神病理学以及生物统计学和数据人类神经科学研究的科学，为她作为一名独立学者的成功职业生涯做好准备。