Although PTSD is a frequent co-morbidity of traumatic brain injury in Veterans, the neurophysiological basis underlying the contribution of TBI to PTSD remains unknown, and there are currently few effective treatments available for this prevalent co-morbidity. A number of human and rodent studies have demonstrated that TBI can exacerbate fear responses, and affect the ability to extinguish a conditioned fear response. Others have demonstrated in PTSD models that there is a shift in the balance between limbic structures (prefrontal cortex, the hippocampus and amygdala) after fear conditioning. Surprisingly, there have been few reports to date of how the network neurophysiology underlying these behavioral changes are affected by TBI. A potential treatment for PTSD using neuromodulation is in trials in Veterans, but we don?t have a clear understanding of how TBI would affect this neuromodulation. There is no accepted theory or supporting data demonstrating how the encoding/recall of fear learning and memory are disrupted by TBI, or how TBI affects the ability to extinguish fear. Therefore, a critical need exists to determine the underlying mechanism of how TBI leads to alteration of fear learning and extinction after traumatic brain injury. Without a deeper understanding of how TBI affects this circuitry, rational design of neuromodulatory and other therapies targeting fear processing remains improbable. The overall objective of the current application is to determine how the coding of fear in extended amygdalar circuitry is affected following TBI, and whether neuromodulation can enable faster fear extinction. Our central hypothesis is that TBI disrupts normal communication between the amygdala and other regions underlying fear memory, which leads to overexpression of fear learning, generalization to other situations, and an inability to extinguish learned fear. This hypothesis is based in part on predictions from our preliminary data demonstrating that injured animals have increased time to extinguish fear, that neurons in the limbic system have different firing properties and entrain to oscillations in a different manner following injury, and others data demonstrating that neuromodulation in the amygdala can eliminate PTSD-like symptoms. In order to test the above hypothesis, we will first determine the mechanism of TBI induced fear responses in rats using simultaneous multi-site recordings and neuropathology. We believe axonal injury affects top down input from the prefrontal cortex, as well as organizing input from the hippocampus (theta oscillations), leading to heightened amygdalar fear responses and poor consolidation of extinction memory. For the first time, we will also test neuromodulation as a treatment to restore normal balance in the extended amygdalar circuitry and restore extinction of fear. We hypothesize that extinction of fear responses in the amygdala can be restored by modulating the remaining prefrontal and/or hippocampal connections to the amygdala. In addition, we will utilize a preclinical pig model of pure diffuse axonal injury to determine whether loss of connections between limbic regions leads to changes in fear memory and an inability to extinguish fear. We believe inertial brain injury induces diffuse axonal injury which disrupts connections between prefrontal cortex, hippocampus and the amygdala, leading to an increase in fear expression and failure of extinction following TBI. Accomplishment of these goals will provide the first detailed physiological analysis of the mechanisms of TBI induced PTSD-like phenotypes across multiple diffuse TBI models. Furthermore, accomplishment of these aims will identify the causal effects of electrical stimulation on these pathways and whether it restores function in rodent models, leading to crucial mechanistic results that can be translated to preclinical and future clinical treatment for comorbid TBI/PTSD. Identification of the neuronal network disruption underlying TBI associated PTSD will not only advance our understanding of the interplay between these disorders, but allow for the development of targeted treatments for this common co-morbidity in our Veterans.
Traumatic brain injury (TBI) is considered the ?signature? injury of the recent US wartime conflicts, with approximately 15% of warfighters experiencing single or multiple mild TBIs (mTBI). PTSD is a frequent comorbidity in this population, with almost 35% of mTBI exposed Veterans reporting qualifying symptoms associated with their service in theater. The presenting symptomatology of PTSD (i.e., emotion dysregulation and cognitive deficits) may have an underlying basis in the biomechanical disruption by TBI of brain regions underlying emotional processing and memory. This same disruption may interfere with effective treatment. Animal models are necessary in order to unravel the effect of TBI on the brain circuitry underlying PTSD. We will therefore utilize high density electrophysiology (recordings) and stimulation in awake behaving rats and pigs to elucidate how TBI affects the circuitry underlying PTSD, the acquisition and extinction of PTSD-like behavioral phenotypes, and to develop a new neuromodulatory treatment for this co-morbidity.
