Alterations of Fear-Associated Learning in Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) are serious pathological conditions that often co-occur following exposure to a traumatic experience. Despite the high comorbidity of mTBI and PTSD, the relationship between these two disorders is poorly understood. One mechanism that may link these two conditions is an alteration in fear-associated learning. Changes in fear-associated learning, specifically in extinction retention, have been reported in PTSD patients and rodent models of PTSD, and we hypothesized that mTBI leads to deficits in fear extinction and extinction retention that predispose patients to PTSD development. We explored the effect of controlled cortical impact (CCI) and single prolonged stress (SPS), models of mTBI and PTSD, on fear-associated learning and extinction in rats. We observed increased freezing in CCI-injured animals throughout the extinction phase in both experiments, suggesting that the rate of fear extinction is impaired following brain injury in rodents. We also investigated changes in fear-associated learning in patients with recent mTBI using a previously-validated fear conditioning task with functional magnetic resonance imaging (fMRI). Subjects in the mTBI group demonstrated greater differential skin conductance response (SCR) to conditioned stimuli during fear extinction versus trauma-exposed controls. Additionally, the mTBI group showed greater differential activation versus controls in dorsal anterior cingulate cortex (dACC) and bilateral insula during late fear extinction and greater activation in dACC and bilateral amygdala during late extinction retention testing. Additionally, differential activation to conditioned stimuli in dACC was directly correlated with differential SCR during late extinction. Together, these results demonstrate altered extinction learning in an animal model of TBI and in patients with recent mTBI, and these differences are associated with hyperactivation of brain regions known to be involved in extinction learning and the fear response.PHDNeuroscience PhDUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/144084/1/jagreco_1.pd