# The Interaction of Stress and Mild Traumatic Brain Injury

> **NIH VA I21** · MIAMI VA HEALTH CARE SYSTEM · 2020 · —

## Abstract

[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.]

## Key facts

- **NIH application ID:** 9883869
- **Project number:** 1I21RX003017-01A1
- **Recipient organization:** MIAMI VA HEALTH CARE SYSTEM
- **Principal Investigator:** COLEEN M. ATKINS
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9883869

## Citation

> US National Institutes of Health, RePORTER application 9883869, The Interaction of Stress and Mild Traumatic Brain Injury (1I21RX003017-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9883869. Licensed CC0.

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