This thesis focuses on the effects of pharmacological and environmental interventions following perinatal prefrontal cortex lesions. Rats given postnatal day 3 medial prefrontal cortex lesions were provided with one of the following treatments: basic fibroblast growth factor (bFGF), complex-housing, tactile stimulation, or a combined treatment of both bFGF and tactile stimulation or bFGF and complex-housing. Rats given postnatal day 3 orbital prefrontal cortex lesions were housed in a complex environment. The findings of these studies suggest that bFGF, complex-housing or tactile stimulation are beneficial after early brain injury. The combined treatment of bFGF with complex-housing provides a synergistic effect, as the combined condition is more advantageous than bFGF alone. In contrast, the combined treatment of bFGF with tactile stimulation produced adverse effects. These results suggest that pharmacological and environmental manipulations change cortical plasticity and therefore functional recovery after neonatal cortical injury. / xv, 177 leaves : ill. (some col.) ; 29 cm.

The purpose of this study was to examine the utility of the Dean-Woodcock Sensory Motor Battery (DWSMB) as a diagnostic tool for identifying individuals with and without closed-head injury, comparing the predictive power of a two- and three-factor representation (DWSMB; Dean & Woodcock, 2003). The current study's major research questions focused on the predictive utility of the structure of the DWSMB. The simplified two-factor model (Total Sensory and Total Motor), based on the DWSMB manual (Dean & Woodcock), was compared to a three-factor theoretical model (Basic Sensory, Higher Sensory and Motor Functions) (R.S.Dean, personal communication, March 29, 2006) for this study. Logistic Regression was used to analyze the data. Results from this study demonstrate that when using the two-factor solution, the overall correct prediction of group membership was 73.8 % (59.4% for CHI and 85.2% for normals). The Total Motor Impairment variable was the only meaningful predictor. The results from the three-factor solution show an 84.2 % overall correct prediction rate (71.4 % for CHI and 95.1 % for normals). The significant contributors for identifying CHI when using the three-factor model included Basic Sensory and Motor Functions. Everything favors the three-factor model as being more precise. All indicators of prediction accuracy and goodness of fit favored the three-factor model. Based on these results, the DWSMB was determined to be a good screening instrument for identifying children in school contexts who should be referred for a neuropsychological examination to confirm pre-existing CHI that interfere with school functioning. / Department of Educational Psychology

No description available.

published_or_final_version / Psychology / Master / Master of Philosophy

Ph.D (Industrial Psychology) / Brain injuries often occur suddenly and without warning, and from that instant, a normal life can be changed. Traumatic Brain Injury (TBI) may result in significant impairment of an individual’s physical, cognitive and psychosocial functioning. Although there is a fair amount of research on the concept of brain damage and the consequent effects on the family and return to work (RTW) prospects, there is far less information available on the actual assessment of workplace capability or workplace potential following the head injury incident. This is important, since the concept of work or job value has been well documented. Employment is far more than just a job; it not only provides for basic sustenance needs and decent living conditions, but also allows someone to fit into the world, create relationships, use talents and skills, learn, grow and build, and develop a sense of identity and belonging. While the value of work is well-documented, the statistics regarding unemployment following a head injury are concerning. It is estimated that approximately 1.5 million Americans sustain head injuries each year, with the majority of these people being under the age of 35 and in their prime years of vocational productivity. A baseline figure of 2% of the American population is currently living with disabilities as a result of head injuries. In South Africa, the rate of occurrence seems to be even more alarming, with published rates of 89,000 cases for 2009. In 2001, this was a baseline figure of 5% of the population living with disabilities resulting from head injuries. Various sources put the occurrence of head injuries in South Africa at 1.5 to 3.5 times higher than the estimated global rate. The negative impact of this on the individual, the family, community and economy is clear.

Every year, in the United States alone, there are 1.7 million incidences of traumatic brain injury (TBI). Unfortunately, despite the tremendous societal and economic cost and decades of research, current pharmacological treatments for TBI are lacking. The specific aims of this thesis are: (1) to determine the efficacy of 17β-estradiol (E2) monotherapy treatment post-TBI, (2) determine if a combination treatment of E2 and memantine provides statistically significant benefits over monotherapy treatments post-TBI, and (3) to investigate the utility of an in vitro model to recapitulate the pathobiology of an in vivo model of TBI and to assess its potential to discover novel and clinically relevant therapeutic targets for future studies. The neuroprotective properties of E2 have been investigated for several decades in several different models including excitotoxicity, ischemia, and TBI. Organotypic hippocampal slice cultures (OHSCs) were mechanically injured at specified strain and strain rates which are relevant to TBI, and the efficacy of E2 post-TBI was investigated. Physiological concentrations of E2 were more effective at preventing cell death than supraphysiological concentrations. Further, GPR30, a novel G protein-coupled receptor, was not activated at physiological concentrations. These results suggest that the classical estrogen receptors (ERs) were primarily responsible for E2-mediated neuroprotection following TBI, and that GPR30 is neither necessary nor sufficient. While monotherapy treatments have shown preclinical success post-TBI, none have been successful in clinical trials. Combination therapies are a promising area of research that focuses on synergistic effects between compounds for significant increases in neuroprotection, potentially resulting in a clinically relevant treatment. A combination treatment of E2 and memantine was statistically more neuroprotective than either monotherapy post-TBI. Using micro-electrode arrays (MEAs), we recorded and quantified increased evoked responses in OHSCs after physiological concentrations of E2 and showed that memantine significantly reduces these effects. Our results suggest a potential combination treatment for TBI and a possible mechanism for its synergistic effects. TBI is a complex injury which initiates a multitude of secondary injuries causing delayed cell death for days or beyond. The utility of in vitro models depends on their ability to recapitulate the in vivo injury cascade after TBI. We used a genome wide approach to study changes in gene expression after injury in both an in vitro model and an in vivo model of TBI to compare the post-TBI pathobiology. There was a strong correlation in gene expression changes between the two models providing confidence that the in vitro model represented the in vivo injury cascade. From these data, we searched for genes with significant changes in expression over time and identified Sorla. Sorla directs amyloid precursor protein (APP) to the recycling pathway by direct binding and away from amyloid beta (Aβ) producing enzymes. Mutations of Sorla have been linked to Alzheimer's disease (AD). We confirmed the down regulation of SORLA expression in OHSCs by immunohistochemistry (IHC) and western blotting. Together, these data suggests that the in vitro model of TBI that was tested strongly recapitulates the in vivo TBI pathobiology and is well-suited for future mechanistic or therapeutic studies. The data also suggest a novel target, Sorla, which may play a role in AD caused by TBI. In conclusion, we discovered a potentially clinically relevant combination treatment of E2 and memantine for post-TBI therapy. We also confirmed that our in vitro model of TBI is well representative of in vivo models, and that relevant, novel targets for future TBI studies can be elucidated with this model. A potential link between AD and TBI was suggested and warrants future study. Together, these studies address the growing public health concern of TBI.

Translocator Protein 18 kDa (TSPO) is a protein that is expressed at low levels in the brain, but upon brain injury or inflammation, increases its expression in the areas of the brain specific to injury. In this way, TSPO can be used as a biomarker of brain inflammation and injury. TSPO is primarily expressed in two cell types, microglia and astrocytes, and is used as a marker of reactive gliosis in various brain pathologies. Currently, there is a paucity of knowledge on the function(s) of TSPO in glial cells. Recent studies using conditional and global TSPO knockout mice have questioned the role of TSPO in translocating cholesterol across the outer mitochondrial membrane as the first step in steroidogenesis. In the brain, microglia and astrocytes exhibit distinct spatial and temporal patterns of TSPO upregulation. These differential patterns are not well characterized across disease models and in particular, are poorly characterized in the early stages of disease, prior to behavioral and clinical disease manifestations. Importantly, these distinct patterns of TSPO upregulation may indicate different functions of TSPO in microglia and astrocytes. We examined TSPO levels in a neurodegenerative transgenic mouse model of Sandhoff disease (SD) and longitudinally compared TSPO levels to behavioral manifestations of disease and other neuropathological endpoints (neurodegeneration, reactive gliosis, ganglioside accumulation). This study confirmed TSPO upregulation prior to neurodegeneration in a brain region-dependent and disease course-dependent way. In brain regions with increased TSPO levels, there was a differential pattern of glial cell activation with astrocytes being activated earlier than microglia during the progression of disease. Immunofluorescent confocal imaging confirmed that TSPO colocalizes with both microglia and astrocyte markers, but the glial source of the TSPO response differs by brain region and age in SD mice. We next wanted to gain insight into the function of TSPO in microglia. We previously demonstrated that TSPO ligands (TSPO-L) (1-100 nM) induced intracellular ROS production which was abrogated by NADPH oxidase (NOX2) inhibitors, thereby indicating an association between TSPO and NOX2. To further elucidate the relationship between TSPO and NOX, we determined the source of ROS production resulting from microglia exposure to TSPO-L. Intracellular and extracellular ROS production was inhibited by NOX inhibitors, but not by a mitochondria permeability transition pore inhibitor, indicating that the source of ROS production is from NOX and not from mitochondria. These findings were confirmed using the mitochondria specific ROS probe MitoSOX. To further explore the TSPO-NOX2 association, we used 3 molecular approaches to examine protein-protein interactions under unstimulated or stimulated conditions (100 ng/mL lipopolysaccharide (LPS) for 18 hours) in primary microglia. 1) Co-immunoprecipitation (co-IP) revealed that the NOX2 subunits, gp91phox (gp91) and p22phox (p22), co-IP with TSPO supporting a protein-protein interaction. TSPO’s association with gp91 and p22 decreased with activation, but TSPO’s association with VDAC, a mitochondrial protein, remained constant. These findings suggest that microglia activation changes the dynamics of the TSPO-NOX2 interaction. 2) Confocal imaging and colocalization analysis of TSPO/gp91 or TSPO/p22 immunofluorescence confirmed that TSPO colocalizes with both NOX subunits. Under stimulated conditions, TSPO associated with gp91 and TSPO associated with p22, exhibit significantly decreased colocalization with VDAC suggesting a movement from the mitochondria to other cellular compartments. 3) Duolink Proximity Ligation Assay confirmed that TSPO interacts with p22, gp91 and VDAC. Our results suggest a novel TSPO-gp91-p22 interaction with VDAC in primary microglia that is disrupted by microglia activation and may be involved with redox homeostasis with significant implications for a new understanding of TSPO glial cell biology. In summary, the present studies have strengthened the use of TSPO as a preclinical biomarker, confirmed its specific spatiotemporal upregulation in two cell types and have provided a new potential function of TSPO in microglia that has the possibility to revolutionize the TSPO field and to inform neurotoxicity assessments and neurological disease treatments.

Cerebral haemodynamic status defined as cerebral vasoreactivity to carbon dioxide and pressure autoregulatory response, have been shown to be affected after traumatic brain injury (TBI) and correlate with the neurological condition and clinical outcome. Therefore, it is important to have a reliable method to determine the cerebral haemodynamic status in brain-injured patients. Blood flow velocity (BFV) measurement by transcranial Doppler ultrasonography (TCD) has been shown to give accurate indication of changes in cerebral blood flow (CBF). Transient hyperaemic response (THR) test with TCD measurement to assess the BFV response of middle cerebral artery to a brief compression of the ipsilateral carotid artery, provides a simple method for repeated assessment of the cerebrovascular autoregulatory reserve in brain injured patients. However, the test has not been validated systematically against classical assessment tests using TCD and gold standard CBF measurement. / The aims of this thesis are (1) to validate the non-invasive TCD and its haemodynamic tests with a more involved gold standard CBF measurement using stable xenon-enhanced computerized tomography. (2) To correlate the cerebral haemodynamic abnormalities with the patterns of neurochemical disturbance detected by intracerebral microdialysis. (3) To investigate the possibility to reverse or minimized the cerebral haemodynamic abnormalities and metabolic derangement by treatment. (Abstract shortened by UMI.) / The goal of intensive care management for TBI is to provide them with a favourable physiological and metabolic environment for recovery of the injured-compromised cells. The development of clinical intracerebral microdialysis has enabled documentation of the metabolic derangement that provides more understanding of the mechanism of brain damage. Continuous measurement of both neurochemical and physiological parameters including CPP defined as mean arterial blood pressure (ABP) minus intracranial pressure, BFV and CBF, enables study of the relationship between metabolic events and physiologic changes. Clinical management of patients with TBI has emphasized on maintaining an optimal cerebral perfusion pressure (CPP). This critical CPP can then be defined by TCD, CBF as well as the metabolic measurements. / Ng Chi Ping. / "June 2005." / Adviser: Wai-sang Poon. / Source: Dissertation Abstracts International, Volume: 67-01, Section: B, page: 0122. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005 / Includes bibliographical references (p. 147-154). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

x, 148 leaves : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D. 1980) from the Dept. of Surgery, University of Adelaide

Author's previously published articles appended. / Bibliography: leaves 292-341. / xviii, 388 leaves ; 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 Psychology, 2005