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

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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.