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

项目摘要 女性在创伤性脑损伤（TBI）后经历更严重的症状和结果， 在临床前研究中，女性性激素具有神经保护作用的共识。多种机制 已经有人提出，推动这种健康差距，包括激素波动在月经周期 进入更年期，倾向于寻求医疗照顾或报告症状，以及 增加神经生物学对损伤的脆弱性。特别是，对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在人类TBI中还没有被彻底研究。 虽然轻度创伤性脑损伤（mTBI）占TBI的大多数，但研究通常集中在特定的 mTBI亚型：运动相关脑震荡。然而，许多人在一次手术中经历了头部创伤。 创伤性事件，如机动车碰撞、身体攻击、性攻击或福尔斯，以及终身 至少经历创伤事件的发生率极高（90%）。作为体育相关的文献， 脑震荡可能并不总是推广到这个创伤暴露的人群，我们的目标是描述性别 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（目的2），并最终评估同时雌二醇水平对TBI的影响 结果和神经影像学标记物（目标3）为了实现这些目标，我将利用一个大型的现有数据集 来自AURORA研究，一项关于创伤后结局的多地点纵向研究。参与者被招募 如果他们在符合资格的72小时内到参与的急诊科（艾德）就诊， 创伤事件，然后随访至创伤后12个月。参与者被评估使用一个 多维范围的工具和措施，以一般的一种，丰富的数据集来研究复杂的， 创伤后神经精神后遗症的并发症状和重叠神经相关因素 跨学科的研究。大约三分之一的AURORA参与者会见了修改后的美国国会议员。 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 TBI的综合体征和症状，必须使用客观标志物在该创伤中建立TBI- 暴露队列。我们建议使用艾德GFAP水平来识别TBI个体，这已经被证明是 在ED就诊后数天内，TBI患者的TBI结局显著升高。 将不仅包括躯体症状（例如，头痛，对光敏感），还有创伤后应激障碍和抑郁症 症状和心理健康相关的生活质量。该项目的完成不仅将使我们的 了解影响TBI结局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、静息态功能性 连接，神经内分泌学，创伤后应激障碍和压力相关的精神病理学，生物统计学和数据 科学人类神经科学研究，准备她作为一个独立的学者成功的职业生涯。

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.