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. A great deal of controversy remains over whether mild traumatic brain injury (mTBI) contributes to the susceptibility for post-traumatic stress disorder (PTSD), or whether mTBI mechanistically underlies some aspects of presenting PTSD symptoms. There is a great deal of overlap in the symptomatology of mTBI and PTSD, suggesting that either a large subpopulation of mTBI exposures are also psychologically traumatic, or that there is an underlying biological substrate after single or multiple mTBIs that predisposes Veterans to PTSD or its associated symptoms. The presenting symptomatology of PTSD (i.e., emotion dysregulation and cognitive deficits) may have an underlying basis in the biomechanical disruption by TBI of the coordination of brain areas for emotional processing and memory. This same disruption may interfere with effective treatment, in particular prolonged exposure (PE), which incorporates an extinction paradigm. Animal models are necessary in order to unravel the effect of TBI on the brain circuitry underlying PTSD. We will therefore utilize the most biomechanically realistic model of diffuse brain injury, the porcine rotational acceleration model, in order to elucidate how mTBI affects the circuitry underlying PTSD and the acquisition and extinction of PTSD-like behavioral phenotypes. We will utilize fear conditioning in order to produce a PTSD-like phenotype in swine. The limbic system, a group of brain regions involved in cognition, memory and processing of emotional salience, is highly linked via oscillatory activity between these networks. Our central hypothesis is that diffuse TBI leads to a disruption within and between areas of the corticolimbic system, increasing dominance of the amygdala over other limbic structures and thus leading to a susceptibility to PTSD-like phenotypes and failure of extinction. TBI may also disrupt the very circuitry required to extinguish post-traumatic symptoms, and adversely affect sleep patterns involved in reconsolidation of memory. We will investigate the mechanisms underlying TBI- related PTSD symptoms and treatment resistance by examining neurophysiological changes in the cortico-limbic system and related behaviors, including sleep-wake architecture, after single and repetitive rotational acceleration injury. To accomplish these aims, swine will be injured repetitively (2x) at acceleration levels inducing mTBI, and then experiments will proceed at multiple time-points post-injury. Multiple electrode arrays that allow for extensive coverage of the cortico-limbic circuit will be implanted under anesthesia and monitored over a period of 3-4 weeks post-injury, during behavioral tasks dependent on cortico-limbic circuitry. Another group of animals will be fear conditioned post-injury in order to detect changes in fear acquisition (i.e., the development of a PTSD-like phenotype) post-TBI. Another group of animals will be fear-conditioned prior to injury so that the effect of subsequent injury (compared to sham injury) on the extinction of fear can be examined. As sleep disruption is a prominent overlapping symptom of PTSD and TBI, all animals, injured and sham injured will be monitored for changes in sleep-wake architecture. Rapid eye movement (REM) s eep macro- and microarchitecture will be examined as there is substantial evidence for REM sleep abnormalities in PTSD. In all experiments, sleep measures will be correlated with electrophysiological measures. The animals will then be sacrificed, and the electrophysiological findings correlated with histopathological analysis of the hippocampus, prefrontal cortex, and amygdala and their connecting axonal tracts. The proposed studies will therefore assess the mechanism(s) underlying comorbid TBI and PTSD by examining the neurophysiological changes in the relevant cortico-limbic networks in a porcine model of diffuse brain injury.

Public Health Relevance

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 the coordination of brain areas for 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 the most biomechanically realistic model of diffuse brain injury, the porcine rotational acceleration model, in order to elucidate how mTBI affects the circuitry underlying PTSD and the acquisition and extinction of PTSD-like behavioral phenotypes.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
5IK2RX001479-04
Application #
9568362
Study Section
Career Development Program - Panel I (RRD8)
Project Start
2015-01-01
Project End
2018-06-30
Budget Start
2018-01-01
Budget End
2018-06-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Philadelphia VA Medical Center
Department
Type
DUNS #
071609291
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wolf, John A; Johnson, Brian N; Johnson, Victoria E et al. (2017) Concussion Induces Hippocampal Circuitry Disruption in Swine. J Neurotrauma 34:2303-2314
Wofford, Kathryn L; Harris, James P; Browne, Kevin D et al. (2017) Rapid neuroinflammatory response localized to injured neurons after diffuse traumatic brain injury in swine. Exp Neurol 290:85-94
Chen, H Isaac; Wolf, John A; Smith, Douglas H (2017) Multichannel activity propagation across an engineered axon network. J Neural Eng 14:026016
Cullen, D Kacy; Harris, James P; Browne, Kevin D et al. (2016) A Porcine Model of Traumatic Brain Injury via Head Rotational Acceleration. Methods Mol Biol 1462:289-324
Wolf, John A; Koch, Paul F (2016) Disruption of Network Synchrony and Cognitive Dysfunction After Traumatic Brain Injury. Front Syst Neurosci 10:43
Chen, H Isaac; Jgamadze, Dennis; Serruya, Mijail D et al. (2016) Neural Substrate Expansion for the Restoration of Brain Function. Front Syst Neurosci 10:1