Brain changes underlying emotional and executive alterations in TBI

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The primary goal of this proposal is to elucidate the possible mechanistic basis of emotional disorders, particularly posttraumatic stress disorder, after mild traumatic brain injury. Problem: Posttraumatic stress disorder (PTSD) is common in military Veterans and often causes chronic suffering including damaging social relationships, employment prospects, health, and overall happiness of those who experience it. Mild traumatic brain injury (mTBI) is a frequent preceding injury and the relationship between injury characteristics associated with mTBI and emotional dysregulation disorders such as PTSD remains unclear, with mixed findings reported in the literature. mTBI can damage important connections between brain regions, especially brain regions critical for emotional experience. Veterans who have suffered one or more mTBIs also are more likely to have other psychiatric conditions, and they also have worse health and social outcomes. Many of these poor outcomes are due to emotional dysregulation. Individuals who have suffered a mTBI or who have PTSD often show changes in brain function in emotional and executive brain regions. Even when their performance on executive tasks is still normal, the underlying brain regions show altered functional relationships including increased activity. Interpretation of these functional changes presents challenges, however. In other populations, these sorts of findings are often associated with pathology or are leading indicators of functional decline. Further, such activity may reflect differences in the capacity to adaptively manage cognitive and emotional resources. When performing emotional tasks, individuals with PTSD show increased activity in emotional brain regions. This may be due in part to reduced executive capacity or to increased demands placed on executive capacity by an overactive emotional system, possibly mediated by dysfunctional neurotransmitter systems. Notably, PTSD is associated with a reduction in the receptors of and the levels of the brain's primary inhibitory neurotransmitter, GABA. Similarly, GABA is reduced after a TBI and this change is associated with a reduced ability to forget fearful memories and to regulate emotions. This overlap in brain changes may suggest a linkage between injury characteristics associated with mTBI and the development of PTSD. Preliminary Work: Consistent with our theoretical model, our pilot data demonstrate damage in limbic and prefrontal connectivity is related to symptoms of PTSD in patients with mTBI. Further, we showed that injury characteristics of mTBI affect performance on emotional tasks. Finally, we demonstrated feasibility for each of the magnetic resonance measures and tasks that we will use in the proposed research. Plan: The proposed investigation will examine the relationship between two key brain networks, limbic (emotional) and prefrontal, which are dysfunctional in individuals with emotional dysregulation and the function of which may be altered after a mTBI. The proposed investigation is also designed to evaluate how GABA mediates these alterations. To test these relationships and changes, we will use functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) to measure regional task-dependent brain activity and regional GABA levels in combat Veterans. We will measure these factors during emotion and cognitive tasks previously reported to be altered in patients with PTSD. We predict that the pattern of activity in executive and emotional brain regions will show changes in activity that relate to PTSD symptoms and to GABA levels. These relationships have not been reported in the literature. If there is a linkage between functional connectivity after mTBI, PTSD and regional GABA levels, there may be potential personalized treatment options that could be harnessed to enact positive changes in these systems and alleviate suffering.