Intra-articular fractures (IAFs) are challenging injuries to study and treat clinically. Following IAF, different joints and even different regions within joints have been shown to have varying degrees of tolerance to injury severity and surgical reduction accuracy. Therefore, to determine the true effects of surgical reduction accuracy on post-traumatic osteoarthritis (PTOA) development, more sensitive and objective measures of articular injury and restoration are needed. To that end, this work details the development of objective measures of injury severity and models of restoration. Two hypotheses were posed: that surgical reduction accuracy is correlated with injury severity, and that injury severity more greatly influences outcomes than the surgical reduction. To quantify the effects of acute injury severity on PTOA development, objective measures of the energy involved in fracturing as well as the degree of damage to the articular surface were created. Differences in the area over which the damage was delivered were also accounted for as a normalization of the fracture energy to a given joint. Inclusion of this latter factor enabled more accurate study of damage to the important areas of the bone. From these measures, a combined severity score was created that could be applied to any IAF. It was demonstrated to be predictive of the degree of PTOA development in the hip, hindfoot, and ankle. The effects of surgical reduction accuracy were measured through contact stress, a measure that detects when forces are concentrated over small areas. When these stresses are too high and persist over time, they are associated with chronic joint degeneration. Therefore, the exposure to the contact stresses during a simulated walking gait after fracture reconstruction was computed for each patient. The over-exposures computed over this gait cycle were strongly associated with PTOA development in all 3 joints studied. By measuring injury severity and reduction accuracy on the same patients with IAFs of the hip, hindfoot, or ankle, relative contributions to PTOA risk were determined for each joint. Significant correlations between injury severity and reduction accuracy were found supporting our first hypothesis. The second hypothesis was refuted, as reduction accuracy was also significantly associated with PTOA development in all 3 joints. An overall model combining the injury severity and reduction accuracy measure for each case was created to assess the total mechanical contributions to PTOA. This model achieved 100% accuracy in the ankle, 88% in the calcaneus, and 91% in the acetabulum.

Mitochondrial dysfunction is a phenomenon observed in models of Traumatic Brain Injury (TBI). Loss of mitochondrial bioenergetics can result in diminished cellular homeostasis leading to cellular dysfunction and possible cellular death. Consequently, the resultant tissue damage can manifest as functional deficits and/or disease states. Therapeutic strategies to target this mitochondrial dysfunction have been investigated for models TBI and have shown promising effects. For this project, we tested the hypothesis that mitoNEET, a novel mitochondrial membrane protein, is a target for pioglitazone mediated neuroprotection. To test this, we used a severe Controlled Cortical Impact (CCI) injury model in mitoNEET null and wild-type mice. We then dosed these animals with pioglitazone or NL-1, which is a compound that has a similar structure to pioglitazone allowing us to hone in one the importance of mitoNEET binding. Wild-type animals treated with the mitoNEET ligands, both pioglitazone and NL-1, had improved mitochondrial function, tissue sparing and functional recovery, compared to mitoNEET null animals. In addition to this specific hypothesis tested, our experiments provided insight casting doubt on the central dogma that mitochondrial dysfunction following TBI is the result of vast oxidative damage and consequential irreversible mitochondrial loss. The data from these studies show that when mitoNEET is targeted with pioglitazone at 12 hours’ post-injury, mitochondrial dysfunction can be reversed. Additionally, when bypassing proteins upstream of Complex I with an alternative biofuel, such as beta-hydroxybuterate (BHB), TBI related mitochondrial dysfunction is once again reversed. This leads to novel hypothesis for future work which posits mitoNEET as a redox sensitive switch; when mitoNEET senses changes in redox, as seen in TBI, it inhibits mitochondrial respiration. When targeted with an agonist/ligand or bypassed with a biofuel TBI mitochondrial dysfunction can be reversed. These studies support the role of mitoNEET in the neuropathological sequelae of brain injury, supporting mitoNEET as a crucial target for pioglitazone mediated neuroprotection following TBI. Lastly, these studies propose a mechanism of TBI related mitochondrial dysfunction which can reversed with pharmacological agents.

Low back pain (LBP) is the top reason for Soldiers to seek medical care and one of the top reasons to be medically discharged. Mental health problems and psychosocial stressors have been increasing in Soldiers and are also top causes for medical discharge. Dysregulated stress has contributed to many Soldiers and Veterans to develop chronic LBP as well as mental health disorders like post-traumatic stress disorder (PTSD). Research suggests that psychosocial characteristics, as opposed to physical factors or tissue health, contribute to chronic pain the most. Focusing entirely on tissues for individuals seeking care for LBP can increase disability and vulnerability. Attributing physical pain to mental health concerns, however, risks stigmatizing patients or making them feel dismissed. The purpose of this dissertation was to develop a pain neuroscience education (PNE) program for Veterans and Soldiers with LBP and stress and determine if PNE is more effective in improving disability, PTSD symptoms, and beliefs about pain compared to traditional education about back pain and stress. This dissertation demonstrated that Veterans with PTSD can comprehend the neuroscience of pain and PTSD at a comparable level to a highly educated Veteran and medical panel without PTSD when adjusting for education. Since a proportion of participants were concerned that using military examples in PNE might increase PTSD symptoms, however, results from pilot testing suggested that the PNE materials developed for this dissertation should be tested in a clinical trial to ensure they do not increase PTSD symptoms. A systematic review and meta-analysis demonstrated that Veterans with PTSD have higher depression and pain-catastrophizing beliefs for a large effect size compared to Veterans without PTSD. Furthermore, Veterans with PTSD have significantly lower pain self-efficacy with a large effect size. Compared to Veterans without PTSD, Veterans with PTSD have higher pain and disability. These results, however, were not confirmed in Veterans presenting to a Physical Therapy clinic. In fact, this dissertation revealed that many of the negative outcomes previously attributed to PTSD in the literature may be due to the correlation between PTSD symptoms and pain-catastrophizing beliefs rather than from trauma. Furthermore, Veterans with chronic LBP do not appear to have different sensitivity levels to pressure based on PTSD symptoms. Finally, the results from a randomized controlled trial provide evidence that PNE greatly improves the confidence of Veterans and Soldiers to increase participation in social, work, and life roles despite the pain as measured by the pain self-efficacy questionnaire. Participants in the experimental group were more likely to achieve a meaningful reduction in disability at the 8-week follow-up compared to the control group. Furthermore, Veterans and Soldiers with LBP were more satisfied with how PNE explains pain and believed the PNE curriculum connected with their military experiences better than traditional psychosocial education about stress. Participants in the experimental arm were less likely to believe that exercise is harmful compared to traditional education. Finally, PNE improved PTSD symptoms beyond the clinically meaningful threshold in the experimental arm. In conclusion, PNE appears to be an effective treatment for PTSD, disability, and pain-related beliefs in Veterans and Soldiers with chronic LBP. These results should be replicated in a larger sample to ensure generalizability beyond the current study.

Goodbye to All That Again concerns the odyssey of an Iraq War veteran who must complete his journey past desert combat and academic strife in order to reclaim his heroic identity. The novel uses a fragmented storytelling mode that offers readers thirteen years of the protagonist’s timeline in a nonlinear sequence. Through this technique, the novel evokes the cognitive disassociation experienced by individuals who suffer Post Traumatic Stress and echoes the postmodern practices employed by American military novelists such as Joseph Heller and Tim O’Brien for the last sixty years. GOODBYE TO ALL THAT AGAIN seeks to intervene in the discourse of the American war novel by updating the depiction of military members from unwilling draftees, the situation Heller and O’Brien portray, to that of career-driven volunteers. The novel also considers adjustment concerns raised by the political correctness movement, a bar to civilian reintegration unknown by prior generations of veterans. In doing so, the writer hopes to adjust the zeitgeist, a major concern of his practice as detailed in his STATEMENT OF PURPOSE, toward a more accurate representation of military members so that society can more effectively meet their needs.

From the day their child is diagnosed, parents of children with special needs are traveling on a journey of extremes. The stress parents experience can lead down many paths filled with stress, worries, and concerns as their constant companion. These conditions exert extreme pressure on parents and can lead to life-altering changes. Parents who are resilient and able to cope with continuous change will ultimately weave through the unknown to a place of positive growth known as post-traumatic growth. The research project was based on qualitative data obtained from interviews with eleven parents of children with special needs. One of the many service professionals these parents interact with on a regular basis is service coordinators. Service coordinators know many personal details related to each family and are in a position to support parents positively to encourage post-traumatic growth. Separate interviews were conducted with nine service coordinators to collect qualitative data for this project. The researcher also conducted an analysis of peer-reviewed research articles and discovered the key factor related to parent’s resilience is encouraging social support provided by peer parents. This increases their resilience and is a critical factor towards achieving positive post-traumatic growth. During research analysis, the researcher found Family-Centered Care to be the most promising method for service coordinators to interact with families and increase the factors of resilience in parents. The current focus at Regional Centers is person-centered thinking. While this practice is beneficial for the clients served, it lacks the holistic consideration of the client and their family together. Future practice recommendations for service coordinators would include policy changes within the Regional Centers to focus on parent’s strengths to discern the supports required to provide the highest quality of care for their children. Training for service coordinators to promote resilience and increase post-traumatic growth in parents would provide additional support in a parent’s life. Support is the key factor in supporting post-traumatic growth. When parents feel supported, they can achieve more and join in stronger collaboration with service coordinators.

Highly comminuted intra-articular fractures are complex and difficult injuries to treat. Once emergent care is rendered, the definitive treatment objective is to restore the original anatomy while minimizing surgically induced trauma. Operations that use limited or percutaneous approaches help preserve tissue vitality, but reduced visibility makes reconstruction more difficult. A pre-operative plan of how comminuted fragments would best be re-positioned to restore anatomy helps in executing a successful reduction. The objective of this work was to create new virtual fracture reconstruction technologies that would deliver that information for a clinical series of severe intra-articular fractures. As a step toward clinical application, algorithmic development benefits from the availability of more precise and controlled data. Therefore, this work first developed 3D puzzle solving methods in a surrogate platform not confounded by various in vivo complexities. Typical tibial plafond fracture fragmentation/dispersal patterns were generated with five identical replicas of human distal tibia anatomy that were machined from blocks of high-density polyetherurethane foam (bone fragmentation surrogate). Replicas were fractured using an instrumented drop tower and pre- and post-fracture geometries were obtained using laser scans and CT. A semi-automatic virtual reconstruction computer program aligned fragment native surfaces to a pre-fracture template. After effective reconstruction algorithms were created for the surrogate tibias, the next aim was to develop new algorithms that would accommodate confounding biologic factors and puzzle solve clinical fracture cases. First, a novel image analysis technique was developed to segment bone geometries from pre- and post-surgical reduction CT scans using a modified 3D watershed segmentation algorithm. Next, 3D puzzle solving algorithms were advanced to obtain fracture reconstructions in a series of highly comminuted tibial plafond fracture cases. Each tibia was methodically reconstructed by matching fragment native (periosteal and articular) surfaces to an intact template that was created from a mirror image of the healthy contralateral limb. Virtual reconstructions obtained for ten tibial plafond fracture cases had average alignment errors of 0.39±0.5 mm. These novel 3D puzzle solving methods are a significant advancement toward improving treatment by providing a powerful new tool for planning the surgical reconstruction of comminuted articular fractures.

In this thesis, I share my personal story of finding healing—post-traumatic growth—after experiencing intimate partner violence seven years ago. Written in Scholarly Personal Narrative format, I dig into my own past, draw upon research and scholarship to better understand and make meaning of and from my experiences, and finally, make connections with other survivors, advocates, and educators through my narrative. I discuss how survivors of intimate partner violence can move closer to healing; provide practical tips on how individuals and educators can support survivors and better understand the complexities of abusive relationships; and explain how educators can use writing, specifically the Scholarly Personal Narrative format, as an avenue for healing and growth for their students in a classroom setting. My thesis is an example of how, when given the opportunity, educators can encourage students to experience post-traumatic growth within the American University.

Traumatic Brain Injury (TBI) is an increasingly diagnosed constellation of injuries derived from acute mechanical trauma to the brain. With the rise of advanced neuroimaging techniques recent focus has oriented primarily towards the mild-moderate range of TBI which previously was missed diagnostically. Characteristically, these advances have shown increasing areas of micro-hemorrhage in susceptible areas of the brain and to date there are no treatment modalities targeting micro-hemorrhages or their sequelae. This dissertation explores the effects of the resulting heme processing response in the days following injury with a particular focus on inducing early heme clearance from the parenchyma using a rat central fluid percussion injury model in the mild-moderate injury range. Since heme is released ~24-48 hours post-injury and is known to be cytotoxic we observed there may be a critical window for treatment to clear heme before it is spontaneously released and to increase the buffering capacity of the tissue. We targeted heme clearance by using drugs known to increased expression of Nrf2, an upstream transcriptional regulator of the canonical heme processing protein heme oxygenase 1 (HO-1), and tracking expression of HO-1, the iron sequestration/storage proteins Lipocalin 2 (LCN2) and Ferritin (FTL), as well as the activity of matrix metalloproteinases 2 and 9 (MMP2, MMP9). We examined both tissue known to be frankly hemorrhagic (the neocortex) as well as tissue lacking any identifiable bleed (the hippocampus). We demonstrated that using the HO-1 inducers Hemin and Sulforaphane in a single dose paradigm given 1 hour post-injury heme clearance was accelerated in the neocortex with the majority of heme pigment processed by 24 hours post-injury. Further there was significant attenuation of protein expression in HO-1 and ferritin as well as the enzyme activity of MMP2 and MMP9 in both the neocortex and the hippocampus. Behavioral attenuation was also seen in both rotarod and Morris water maze tests. While we intended to target hemorrhagic processing after injury, and indeed demonstrated improved clearance of heme from post-injury hemorrhagic regions of the brain, in both tissues studied we observed remarkably similar responses to the drugs utilized in protein expression, enzyme activity, and behavioral improvement which may suggest a globally improved pathologic state or that there are unidentified pathologic micro-hemorrhages or leaky vessels which extend further into the brain parenchyma than currently identified.

A growing body of evidence implicates the importance of the endogenous cannabinoid 2-arachidonyl glycerol (2-AG) in memory regulation. The biosynthesis of 2-AG occurs primarily through the diacylglycerol lipases (DAGL-α and -β), with 2-AG serving as a bioactive lipid to both activate cannabinoid receptors and as a rate limiting precursor for the production of arachidonic acid and subsequent pro-inflammatory mediators. Gene deletion of DAGL-α shows decrements in synaptic plasticity and hippocampal neurogenesis suggesting this biosynthetic enzyme may be important for processes of normal spatial memory. Additionally, 2-AG is elevated in response to pathogenic events such as traumatic brain injury (TBI), suggesting its regulatory role may extend to conditions of neuropathology. As such, this dissertation investigates the in vivo role of DAGL-α and -β to regulate spatial learning and memory in the healthy brain and following neuropathology (TBI). The first part of this dissertation developed a mouse model of learning and memory impairment following TBI, using hippocampal-dependent tasks of the Morris water maze (MWM). We found modest, but distinct differences in MWM performance between left and right unilateral TBI despite similar motor deficits, histological damage, and glial reactivity. These findings suggest that laterality in mouse MWM deficit might be an important consideration when modeling TBI-induced functional consequences. The second part of this dissertation work evaluated DAGL-β as a target to protect against TBI-induced learning and memory deficit given its selective expression on microglia and the role of 2-AG as a precursor for eicosanoid production. The gene deletion of DAGL-β did not protect against TBI-induced MWM or motor deficits, but unexpectedly produced a survival protective phenotype. These findings suggest that while DAGL-β does not contribute to injury-induced memory deficit, it may contribute to TBI-induced mortality. The third and final set of experiments investigated the role of DAGL-α in mouse spatial learning and memory under physiological conditions (given the predominantly neuronal expression of DAGL-α). Complementary pharmacological and genetic manipulations produced task specific impaired MWM performance, as well as impaired long-term potentiation and alterations to endocannabinoid lipid levels. These results suggest that DAGL-α may play a selective role in the integration of new spatial information in the normal mouse brain. Overall, these data point to DAGL-α, but not DAGL-β, as an important contributor to hippocampal-dependent learning and memory. In contrast, DAGL-β may contribute to TBI-induced mortality.

According to the Center for Disease Control’s (CDC) report to the Congress, there are 2.2 million emergency department visits; 80,000 hospitalizations; and 50,000 deaths each year due to traumatic brain injury. Adults 65 years and older account substantially for the majority of the hospitalization and deaths. Over 70% of the traumatic brain injuries of the older adults are classified as mild to moderate; however, even with these milder injuries, older adults present with a significantly higher morbidity and mortality compared to all other age groups (LeBlanc et al., 2006). With that in mind, it seems essential to develop a deeper understanding of the causes behind higher mortality and morbidity of traumatic brain injury in the elder population. It is well documented that increased age is accompanied by increased CNS inflammation. Recently, our laboratory showed that inflammation drives brain pathology. Specifically, we reported that the axon initial segment of cortical neurons was structurally and functionally compromised in an inflamed CNS environment. With this in mind, we proposed that age-related inflammation predisposes that brain to exacerbated pathologic consequence. To test this hypothesis, we administered a mild to moderate central fluid percussion brain injury in aged and young adult mice. Using immunocytochemical labeling against the axon initial segment protein ankyrinG combined with laser scanning confocal microscopy, we quantitatively compared axon initial segment number and length between age groups and within age groups with and without injury. Additionally, we also quantified global axonal pathology by immunolabeling for amyloid precursor protein (APP) positive swelling as an indicator of compromised axonal transport. We proposed that ankyrinG labeling will be both reduced in the aged injured mice compared against aged uninjured, young adult injured and young adult non-injured. We observed a significant increase in APP accumulations due to injury independent of aging, and due to aging independent of injury. No significant changes in the effect of injury between young and aged injured mice were observed. Although AIS length was not altered between age groups following injury, our results demonstrate that the elderly population presents with significantly shorter initial segments. The consequence of this shortening is not clear but may reflect compensatory changes in the brain to maintain homeostasis.