Traumatic brain injury (TBI) is a serious public health concern. Although moderate and severe forms of TBI receive considerable attention, mild TBI accounts for the majority of all injuries. The first two aims of this work used a rodent model of mild blast to simulate primary injury (damage from the blast wave only). The first aim evaluated potential changes in interneurons containing the calcium-binding proteins calretinin or parvalbumin. In addition, morphological changes in astrocytes and microglia were assessed. Brains were analyzed 48 hours and one month following exposure to single or repeated blasts, with a focus on the hippocampus due to its integral role in learning and memory. Results showed significant region-specific alterations in microglia morphology 48 hours following blast. The absence of structural alterations in microglia one month following blast indicated that the regional hippocampal vulnerability may be transient. The second aim compared glial morphologies in the retina and brain (the lateral geniculate nucleus, superior colliculus, and visual cortex) 48 hours or one month following multiple blasts. Fiber degeneration has received considerable attention, however, less is known about the status of glia throughout the visual pathway following mild blasts. Although no structural alterations were detected, it is possible that alterations in glia occurred at a more acute time scale as changes in glia can be rapid and reversible. The final aim of this work focused on the immunocytochemical characterization of tau pathology in the visual cortices of human postmortem brains with advanced chronic traumatic encephalopathy (CTE). CTE is a devastating tauopathy associated with mild, repetitive TBIs. Although visual deficits are reported in CTE, the primary visual cortex is often spared. The main hypothesis under investigation was whether visual association areas would have tau pathology, despite sparing of primary visual cortex. In addition, a sub-class of interneurons containing parvalbumin was used to evaluate a potential cell-specific vulnerability. Results showed increased tau pathology in visual association areas in advanced CTE, that was largely absent from the primary visual cortex. There was no effect on parvalbumin positive interneurons. The results of this work provides valuable insight regarding potential cell-specific resistance to CTE pathology. / 2018-11-03T00:00:00Z

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Blast-induced traumatic brain injury and hearing loss are two of the most common forms of the “invisible wounds of war” resulting from the United States’ Global War on Terror. Several published studies have been confirming recent reports from VA healthcare centers of blast-exposed Service Members complaining of auditory problems despite having hearing that is, for all intents and purposes, normal. Most common among these complaints is problems understanding speech in crowded and noisy situations. We hypothesized that problems with speech comprehension could either be the result of 1) damage to sensory areas in the auditory periphery or 2) blast-induced traumatic brain injury (TBI) to cortical networks associated with the processing of attention, memory, and other executive functions related to the processing of speech and linguistic information. In Chapter 1 of this thesis, we found that in a population of blast-exposed Veteran Service Members, problems with speech comprehension in noise were due to cognitive deficits likely resulting from issues related to their post-traumatic stress disorder (PTSD) diagnoses. Chapter 2 takes and expanded look at the topics of Chapter 1 with a more comprehensive battery of audiological, electrophysiological, and neuropsychological tests in active duty Service Members with and without a history of blast exposure. Unlike in veterans with PTSD, we found subclinical levels of peripheral auditory dysfunction, as well as evidence of compromised neural processing speed in the blast-exposed group. These deficits were also consistent with poorer performance on a standardized speech-in-noise test and lower self-reported ratings on an abbreviated version of the Speech, Spatial, and Qualities (SSQ) of Hearing questionnaire (Gatehouse and Noble, 2004). In Chapter 3,we modeled outcomes from the SSQ survey using objective measures of hearing function related to audibility, distortion of the neural representation of sound, attention, age, and blast status. We found for all subjects age and high frequency hearing thresholds predicted survey outcomes related to everyday listening ability. Within non-blast controls, however, measures of attention could differentiate between good and exceptional listening ability. Results from blast exposed subjects remained inconclusive. Collectively, these findings highlight the need for audiologists to take into account more than audiometric measures alone when diagnosing and treating hearing dysfunction in this unique and specialized patient population.

Traumatic brain injury (TBI) is a major medical concern that has demonstrated to be particularly challenging to treat because of the disparity amongst injury modes and severities. Increased use of explosive devices during combat has caused blast TBI (bTBI) to become a widespread consequence in military and Veteran populations, and impact-related trauma from contact-related sports or motor vehicle accidents has made mild impact-induced TBIs (concussion) a major health problem. There is a high risk for those who have sustained a TBI to develop behavioral and cognitive disorders following injury, and these symptoms can present as delayed onset, causing diagnosis to be a major feat when planning for treatment and long-term healthcare. Both preclinical and clinical studies report the neuropathological changes following TBI, yet investigating the distinct mechanistic changes in blast and impact trauma that contribute to pathological disparities has yet to be elucidated. Microglia dynamics play a key role in initiating the inflammatory response after injury, as microglia become activated by undergoing morphological changes that influence their function in the injured brain, and unique signaling pathways influence their functional inflammatory states. While previous literature report on the unique responses of microglia, their mediated-inflammatory responses are still not well defined. This work aimed to investigate the acute and subacute responses of microglia to injury through their diverse activation states following blast and impact trauma. The work herein employed rodent models to investigate these changes, finding that microglia activation was spatially and temporally heterogeneous within and across injury paradigms. Three days following bTBI, activated microglia in the cortex displayed morphologies similar to microglia that are known to increase their interactions with dysfunctional synapses, while dystrophic microglia were prevalent in the hippocampus seven days following injury. Moreover, transhemispheric changes in microglia activation were noted following impact TBI, with stressed/primed microglia responding to immune challenges of the cortex at three days, whereas a unique morphological state that was markedly different from those traditionally reported in CNS injury and disease was present within the hippocampus three- and seven-days following injury. State-of-the-art cell sorting techniques were used for in vivo analysis of microglia, which also exhibited that functional changes of microglia vary between injury paradigms, providing insight into how differences in primary insult may elicit distinct signaling pathways involved in microglia-mediated inflammatory responses. These in vivo studies were then crucial in understanding the malleable responses of microglia to complex injuries such as "blast plus impact" TBI, indicating that phenotypic changes in microglia following this injury are also unique and spatially heterogeneous. To date, therapeutic efforts for TBI are limited due to the lack of understanding the underlying mechanisms that influence TBI pathology. This work also investigated novel therapeutic targets, noting that administration of polyester nanoparticles restored microglia to baseline levels following impact. The fundamental research presented in this study is innovative and advantageous as it can provide essential data into targeted and personalized treatments that can improve long-term healthcare and ultimately, the quality of life for those suffering from a TBI. / Doctor of Philosophy / Traumatic brain injury (TBI) is a major medical concern that has demonstrated to be particularly challenging to treat because of the differences in injury modes and severities. Increased use of explosive devices during combat has caused blast TBI (bTBI) to become a widespread result in military and Veteran populations, and impact-related trauma from contact sports or motor vehicle accidents has made mild impact-induced TBIs (concussion) a major health problem. There is a high risk for those who have sustained a TBI to develop behavioral and cognitive disorders following injury, and these symptoms can present later on, causing diagnosis to be a major feat when planning for treatment and long-term healthcare. Microglia play a key role in inducing the inflammatory response after injury, as they change shape and size, which then influences their function in the injured brain. Although prior research reports on the unique responses of microglia, their effects on inflammation following TBI are still not well defined. This work aimed to investigate the early responses of microglia to injury through their diverse activation states following blast and impact trauma. The experiments in this study used animal models, finding that microglia activation can be distinct across time and brain regions, which may be injury-type-specific. To date, therapeutic efforts of TBI are limited due to the lack of understanding the underlying mechanisms that influence TBI pathology. This work also investigated beneficial treatments for TBI, noting that administration of nanoparticles helped restore microglia to levels similar to the control group. The fundamental research presented in this study is innovative and important as it can provide essential data into targeted and personalized treatments that can improve long-term healthcare and ultimately the quality of life for those suffering from a TBI.

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This lecture takes a dual-targeted approach in: 1) acquainting the audience with newer neuroimaging techniques applied to the consequences of vestibular dysregulation following noise or blast-induced mild traumatic brain injury (mTBI); and 2) considers treatment and rehabilitation modalities of vestibular and balance dysfunction in order to help veteran’s resume normal activities-of-daily-living. Relevant examples from each targeted lecture will be provided. Intended Audience: Professionals interested in the area of vestibular and balance assessment, neuroimaging, and rehabilitation.

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