Traumatic brain injury (TBI) is the signature injury of the ongoing military conflicts in the Middle East and Afghanistan, largely due to the use of improvised explosive devices (IEDs), which have affected soldiers and civilians alike. Blast-induced TBI (bTBI) biomechanics are complex and multiphasic. While research has clearly demonstrated the negative effects of penetrative (secondary blast) and inertia-driven (tertiary blast) injury, the effect of shock wave loading (primary blast) on the brain remains unclear. Combined primary-tertiary blast exposure in vivo has been reported previously to alter brain function, specifically hippocampal function; however, it is extremely difficult to deliver primary blast exposure in isolation with an in vivo injury model. The research presented in this thesis utilized a custom-designed in vitro blast injury model to deliver military-relevant shock wave exposures, in isolation, to organotypic hippocampal slice cultures (OHSCs). To contextualize blast-induced pathobiology with previous TBI studies, the first goal of this thesis was to experimentally characterize the deformation profile induced in OHSCs with our blast injury model. Using stereoscopic, high-speed cameras and digital image correlation to calculate strain, we found that our blast model induced low strain magnitudes (<9%) but at high strain rates (25-86s-1), which aligned closely with associated computational simulations of our model. The second aim was to determine if primary blast was capable of altering hippocampal electrophysiological function. We exposed OHSCs to a range of shock intensities and found, using a micro-electrode array system, that long-term potentiation (LTP), a measure of synaptic plasticity, was very sensitive to primary blast exposure; a threshold for disruption of LTP was found between 9 and 39 kPa•ms impulse. Alternative measures of basal electrophysiology were less sensitive than LTP. Blast exposure significantly reduced LTP between 1 and 24 hours post-injury, and this deficit persisted through 6 days post-injury. Depending on shock intensity, LTP spontaneously recovered 10 days post-injury. The third aim was to explore the cellular mechanisms for blast-induced LTP deficits. Using a chemical LTP induction protocol, blast exposure altered key proteins necessary for the induction of LTP by 24 hours post-injury including, postsynaptic density protein-95 (PSD-95), a major scaffolding protein that organizes the postsynaptic density (PSD), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptor 1 (AMPA-GluR1), and stargazin, an auxiliary GluR1 protein that binds AMPA-GluR1 to PSD-95. Modulation of the cyclic adenosine monophosphate (cAMP) pathway reversed the observed effects of blast on LTP. We theorized that blast-induced disruption of PSD-95 prevented translocation, and subsequent phosphorylation, of GluR1-containing AMPARs to the postsynaptic membrane, which, in turn, prevented potentiation. The final aim was to investigate the efficacy of phosphodiesterase-4 (PDE4) inhibitors, which block degradation of cAMP, as a therapeutic strategy. When delivered immediately following primary blast injury, multiple PDE4 inhibitors proved efficacious in restoring LTP measured 24 hours post-injury. Roflumilast, a Food and Drug Administration-approved PDE4 inhibitor, was effective when delivered at a clinically relevant concentration (1nM) and at a delayed time point (up to 6 hours). Roflumilast reversed blast-induced changes in expression/phosphorylation of the key LTP protein targets. We hypothesized that maintenance of PSD-95 drove the observed therapeutic effect. Greater work is necessary to determine how blast exposure degrades PSD-95 and how roflumilast prevented these detrimental effects. This thesis has shown that primary blast exposure can negatively alter neurological function, as well as protein expression and phosphorylation. These studies expand the understanding of primary blast injury mechanisms, provide computational models with important tissue-level tolerance criteria, inform protective equipment design, inform clinical care guidelines for bTBI, and present a promising therapeutic candidate for further clinical investigation.

OF DIPLOMA THESIS Title of diploma thesis: Clinical Utility of Rivermead Behavioural Memory Test in Patients after Brain Damage Objective: The main goal of this diploma thesis was to monitor the relationship between memory functions measured by the Rivermead Behavioral Memory Test (RBMT-3) and their subsequent influence on occupational performance in ADL (pADL) in patients after brain damage. The partial objective was to determine whether self-sufficiency in ADL can be predicted from RBMT-3 results. The last partial goal was to create a working version of the RBMT-3 and translate it from the original English version. Methods: The research group consisted of 40 probands (22 males and 18 females) after brain damage. For data collection, the Rivermead Behavioral Memory Test (RBMT-3) for assessing the memory function level was used. FIM (version 5.2) was used for evaluating the level of occupational performance in ADL (pADL). Hypothesis verification was performed by correlation analysis and corrected Spearman's correlation coefficient and p-values. For this pre- research, the level of significance α1 < 0.05 and α2 < 0.01 was chosen. Results: The pre-research did not confirm the dependence between the RBMT-3 memory level and the level of self-sufficiency measured by FIM. The P value (p = 0.526) from the...

OF DIPLOMA THESIS Title of diploma thesis: Clinical Utility of Rivermead Behavioural Memory Test in Patients after Brain Damage Objective: The main goal of this diploma thesis was to monitor the relationship between memory functions measured by the Rivermead Behavioral Memory Test (RBMT-3) and their subsequent influence on occupational performance in ADL (pADL) in patients after brain damage. The partial objective was to determine whether self-sufficiency in ADL can be predicted from RBMT-3 results. The last partial goal was to create a working version of the RBMT-3 and translate it from the original English version. Methods: The research group consisted of 40 probands (22 males and 18 females) after brain damage. For data collection, the Rivermead Behavioral Memory Test (RBMT-3) for assessing the memory function level was used. FIM (version 5.2) was used for evaluating the level of occupational performance in ADL (pADL). Hypothesis verification was performed by correlation analysis and corrected Spearman's correlation coefficient and p-values. For this pre- research, the level of significance α1 < 0.05 and α2 < 0.01 was chosen. Results: The pre-research did not confirm the dependence between the RBMT-3 memory level and the level of self-sufficiency measured by FIM. The P value (p = 0.526) from the...

Memory impairment is an outcome of Traumatic Brain Injury (TBI), and associated with lower levels of post-morbid adjustment. This research isolated the memory impairment of retrieval deficit, and examined the efficacy of cues and mnemonics in remediating the impairment. Thirty-three male and female TBI survivors, 18 to 71 years old, were pre-tested for attention (COPY), short-term memory (SD), long-term memory (LD) and recognition memory (RS) employing the Rey Osterrieth Complex Figure Test (CFT), and Subtest. Sixteen subjects demonstrating a retrieval deficit were administered the post-test, with even random assignment into four treatment conditions: a control group (CONTROL), a group administered cues (CUES), a group administered mnemonics {MNEM), and a group administered mnemonics and cues (BOTH) (n = 4). A MANOVA revealed a significant effect of TRIAL (p5.05), no significant effect of TREATMENT, and no interaction. A power analysis indicated the lack of TREATMENT effect could be the result of sample size. Post-hoc t tests revealed a difference across TRIAL for SD and LO in the two experimental conditions which utilized mnemonics. The sample was divided into two groups according to subjects' level of functioning (HIGH and LOW). A MANOVA showed main effects for LEVEL for SD and RS, for TRIAL for SD, LO, and RS, and a LEVEL by TRIAL interaction for COPY (R

Doctor of Philosophy (PhD) / Proteomics is rapidly achieving recognition as a complimentary and perhaps superior approach to examine global changes in protein abundance in complex biological systems and the value of these techniques in neuropsychiatry is beginning to be acknowledged. Characterizing the brain’s regional proteomes provides a foundation for the detection of proteins that may be involved in disease-related processes. Firstly, optimal conditions were achieved for the application of two dimensional-gel electrophoresis (2D-GE)-based proteomics with postmortem human brain tissue. These optimized techniques were then applied to soluble fractions of adjacent grey and white matter of a single cytoarchitecturally defined area (Brodmann area 9; BA9) and of two adjacent regions of frontal white matter (BA9 and CC body) from healthy individuals. These normative proteomic comparisons highlighted the importance of correct tissue sampling, i.e. proper separation of regional white matter, as heterogeneity in the respective proteomes was demonstrated. Furthermore, they stressed the necessity for future molecular brain mapping studies. The main focus of this thesis however, was to examine the proteomes of brain regions specifically vulnerable to alcohol-induced damage underlying cognitive dysfunction. Alcoholic patients commonly experience mild to severe cognitive decline. It is postulated that cognitive dysfunction is caused by an alcohol-induced region selective brain damage, particularly to the prefrontal cortex. The cerebellum is increasingly recognized for its role in various aspects of cognition and alcohol–induced damage to the cerebellar vermis could indirectly affect neurocognitive functions attributed to the frontal lobe. We used a 2D-GE-based proteomics approach to compare protein abundance profiles of BA9 grey and white matter and the cerebellar vermis from human alcoholics (neurologically uncomplicated and alcoholics complicated with liver cirrhosis) and healthy control brains. Among the protein level changes observed are disturbances in the levels of a number of thiamine-dependent enzymes. A derangement in energy metabolism perhaps related to thiamine deficiency seems to be important in all regions analysed, even where there are no clinical or pathological findings of Wernicke-Korsakoff Syndrome. Evidence of oxidative changes was also seen in all regions and effects of liver dysfunction in the vermis found. However, overall, these results highlight the complexity of this disease process in that a number of different proteins from different cellular pathways appear to be affected. By identifying changes in protein abundance levels in the prefrontal grey and white matter and the cerebellar vermis, hypotheses may draw upon more mechanistic explanations as to how chronic ethanol consumption causes the structural and functional alterations associated with alcohol-related brain damage. Furthermore, by comparing these results, we may be able to isolate disturbances in molecular pathways specific to the brain damage caused by alcohol, severe liver dysfunction and thiamine deficiency.

Includes list of articles published or accepted for publication during the period of PhD candidature. / "July, 2004" / Includes bibliographical references (leaves 255-293) / xxviii, 293 leaves : ill., plates (col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Pathology, 2004?

Stroke is a widespread disease in Sweden. Nurses play a central part for those who suffer from a stroke irrespective of where in the care chain they meet. To be able to meet the patients’ need of care the nurse must understand his/her lifeworld. Each and every patient is unique and the experience of being struck by a stroke depends on personality and life situation. Those who suffer from aphasia are usually excluded in research and therefore there is lack of improtant knowledge. The aim of this study is to describe the experiences of suffering from and living with a stroke. By studying autobiographies the opportunity has opened to share the experiences of patients suffering from aphasia. To suffer from stroke is a big changeover in life and gives visible and invisible disabilities. These disabilities limit them in their every day life. Nursing staff becomes authorities and it’s important that the staff provides time for discussions. A fruitful discussion reduces suffering and creates feelings of being noticed and involvement. The result shows that those who suffer longs and endeavours for living life as normal as possible. / I Sverige är stroke en av våra stora folksjukdomar. De som drabbas är en stor patientgrupp och sjuksköterskor har en central roll i deras omvårdnad oavsett vart i vårdkedjan de befinner sig. För att kunna bemöta patientens behov av omvårdnad måste sjuksköterskan sätta sig in i patientens livsvärld. Varje patient är unik och upplevelsen av att drabbas är olika beroende på personlighet och livssituation. Personer med afasi har tidigare uteslutits i studier vilket gör att det saknas forskning inom ett stort och viktigt område. Syftet med studien är att beskriva människors upplevelser av att drabbas av och leva med stroke. Genom att studera självbiografier tillkom även möjligheten att ta del av patienter med afasis upplevelser. Att drabbas av stroke är en stor omställning i livet och ger synliga och osynliga handikapp som begränsar i vardagslivet. Vårdpersonal blir auktoriteter i deras liv, och det är viktigt att de har tid för samtal med de drabbade. Ett gott samtal upplevs minska lidande och skapar känslan av att vara sedd och delaktig i vården. Resultatet visar att de drabbade längtar och strävar efter att leva livet så normalt som möjligt.

Traumatic brain injury (TBI) is a major health and socioeconomic concern in the United States and across the globe. Experimental models of TBI are used to study the mechanisms underlying cell dysfunction and death that result from injury, the functional deficits that result from injury, and the potential of various therapies to treat injury. This thesis explores the fundamental mechanical damage associated with brain trauma, investigating the effects of mechanical deformation on neurons at the molecular, cellular, tissue, and animal levels. First, a novel hydrogel system was developed to support 3-D neuronal cultures, and the cultures were studied in an in vitro model of neuronal injury. The dependence of cell viability on hydrogel stiffness and extracellular matrix ligand concentration revealed a role for molecular interactions in the cellular response to injury. Subsequently, in a rat model of TBI neuronal plasma membrane damage was observed coincidentally with cell death within the hippocampus; however not all permeable cells died, suggesting a complex role for plasma membrane damage in neuronal degeneration. The spatial profile of permeable cells in the hippocampus reveals further heterogeneity of neuronal plasma membrane damage, with populations of cells in certain hippocampal subregions exhibiting an increased vulnerability to plasma membrane damage. These observations support recent finite element model predictions of strains in the brain during injury. Finally a system for measuring locomotor disturbances is used for the first time following brain injury. Continued investigation of how neurons deform and fail mechanically will contribute to the understanding of the pathophysiology of brain injury and may help identify potential therapeutic targets.

Thesis (Ph.D.)--University of Nebraska-Lincoln, 2009. / Title from title screen (site viewed October 15, 2009). PDF text: vi, 113 p. : ill. (some col.) ; 1 Mb. UMI publication number: AAT 3366687. Includes bibliographical references. Also available in microfilm and microfiche formats.

Thesis (Ph. D.)--University of Missouri--Columbia, 2003. / Typescript. Vita. Includes bibliographical references (leaves 309-329).