[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.]
Most Veterans fully recover after a concussion or mild traumatic brain injury (TBI), but there is a subset of Veterans that have persistent symptoms such as cognitive problems for weeks to months after the injury. This proposal will study if pre-exposure to a stressful environment during childhood affects recovery after mild TBI and develop a rehabilitation training protocol to improve learning and memory in the recovery period.
