<p>Explosions are associated with more than 80% of the casualties in the Iraq and Afghanistan wars. Given the widespread use of thoracic protective armor, the most prevalent injury for combat personnel is blast-related traumatic brain injury (TBI). Almost 20% of veterans returning from duty had one or more clinically confirmed cases of TBI. In the decades of research prior to 2000, neurotrauma was under-recognized as a blast injury and the etiology and pathology of these injuries remains unclear.</p><p>This dissertation used the finite element (FE) method to address many of the biomechanics-based questions related to blast brain injuries. FE modeling is a powerful tool for studying the biomechanical response of a human or animal body to blast loading, particularly because of the many challenges related to experimental work in this field. In this dissertation, novel FE models of the human and ferret head were developed for blast and blunt impact simulation, and the ensuing response of the brain was investigated. The blast conditions simulated in this research were representative of peak overpressures and durations of real-world explosives. In general, intracranial pressures were dependent on the peak pressure of the impinging blast wave, but deviatoric responses in the brain were dependent on both peak pressure and duration. The biomechanical response of the ferret brain model was correlated with in vivo injury data from shock tube experiments. This accomplishment was the first of its kind in the blast neurotrauma field.</p><p>This dissertation made major contributions to the field of blast brain injury and to the understanding of blast neurotrauma. This research determined that blast brain injuries were brain size-dependent. For example, mouse-sized brains were predicted to have approximately 7 times larger brain tissue strains than the human-sized brains for the same blast exposure. This finding has important implications for in vivo injury model design, and a scaling model was developed to relate animal experimental models to humans via scaling blast duration by the fourth-root of the ratio of brain masses. </p><p>This research also determined that blast neurotrauma is correlated to deviatoric metrics of the brain tissue rather than dilatational metrics. In addition, strains in the blasted brain were an order-of-magnitude lower than expected to produce injury with traditional closed-head TBI, but an order-of-magnitude higher in strain rate. The 50th percentile peak principle strain metric of values of 0.6%, 1.8%, and 1.6% corresponded to the 50% risk of mild brain bleeding, moderate brain bleeding, and apnea respectively. These findings imply that the mechanical thresholds for brain tissue are strain-based for primary blast injury, and different from the thresholds associated with blunt impact or concussive brain injury because of strain rate effects.</p><p>The conclusions in this dissertation provide an important guide to the biomechanics community for studying neurotrauma using in vivo, in vitro, and in silico models. Additionally, the injury risk curves developed in this dissertation provide an injury risk metric for improving the effectiveness of personal protective equipment or evaluating neurotrauma from blast.</p> / Dissertation

Introduction-Physical activity can reduce the risk of contracting many of the 'diseases of the sedentary', such as coronary heart disease and cancer (Blair et al., 1996). Recognition of this protective effect has led to the development of many programmes designed to promote the benefit of participation in sport and physical exercise (Hillary Commission, 1993; Nicholl et aI., 1995). With participation in sport, especially contact sport, the risk for injuries increases, including injuries to the head and neck (Wilberger, 1993; Wekesa et al., 1996; Pettersen, 2002). Mild traumatic brain injuries (MTBI) or concussion as used interchangeably in the literature (Maroon et al., 2000; Wills & Leathem, 2001) are an important public health concern, due to the high incidence and frequently persisting symptomatology (Evans, 1992). Mild traumatic brain injury is defined as a complex patho-physiological process affecting the brain induced by traumatic biomechanical forces (Aubry et al., 2002; McCrory et al., 2004). A sub-concussive injury or very mild traumatic brain injury (vMTBI) may be defined as an apparent brain insult with insufficient force to cause hallmark symptoms of concussion (Jordan, 2000; Webbe & Bath, 2003). The high incidence of sport related head injuries in South Africa is alarming, although the prevalence thereof is unknown and difficult to assess, as the seemingly trivial injuries frequently remain unreported (Roux et al., 1987). This is especially applicable in sport where a milder form of head injury is common. This is cause for concern as cumulative head injuries traditionally regarded as trivial or 'minor' may result in players running the risk of increasingly negative consequences following repetitive 'minor' head injuries. In contact sport such as rugby, players are at great risk of sustaining repetitive mild traumatic brain injuries. The negative outcome following these repetitive minor head injuries has been demonstrated by numerous studies on boxers and other athletes exposed to repeated MTBI and vMTBI (McLatchie et aI., 1987). The incidence of vMTBI has not yet been researched in school rugby and this study is the first to report the incidence of vMTBI in a secondary school rugby team. Obiectives - The objectives of this study were to determine the incidence, the neuropsychological consequences and the effect on the academic performance of repeated mild (MTBI) and very mild traumatic brain injuries (vMTBI) in a secondary school rugby team during one playing season. Methods - A cohort of 35 secondary school male rugby players divided into a vMTBI (group 1) (n=26) and a MTBI (group 2) (n=9) from a local secondary school's first and second team, was followed for a full competitive season by a trained Biokineticist, who was present at all the games and contact sessions played. All vMTBI and MTBI and the severity of these injuries were documented. A control (group 3) that consisted of 10 secondary school non-rugby players were compared with the vMTBI and MTBI groups. The incidence of repeated MTBI and vMTBI in a secondary school rugby team were gathered by questionnaires and observation next to the field by a trained Biokineticist. Pre-season and post-season neuropsychological tests were conducted on the research groups and the control group. The neuropsychological tests that were conducted on the three groups were the Colour Trial Test 1 and 2 (CTT 1 + 2), the Symbol Digit Modalities Test (SDMT), the Wechsler Memory Scale-Revised (WMS-R) and the Standardised Assessment of Concussion (SAC). After each match played throughout the season the research group also completed a SAC test. The academic results of the final examination (year 1) of the year of the specific rugby season were obtained, as well as the academic results of the final examination of the preceding two years (year 2 and 3). The programme STATISTICA (version 7.0, Stat soft, Tulsa, OK) was used to analyse the data. Descriptive statistics, one-way ANOVA's, two-way repeated measures ANOVA's, Post-hoc Tuckey HSD analysis and Pearson's product moment correlation were used for all the statistical analyses. Results - This study of a secondary school rugby team has shown 726 vMTBI's and 18 MTBI's throughout one rugby season. This relates to 1951 vMTBI's per 1000 player hours and 48 MTBI's per 1000 player hours. Reductions in delayed memory (p=O.O1)from preseason to post-season in a group of players with repetitive vMTBI's during a single rugby season were found. This was the first evidence of possible neurocognitive deficits towards delayed memory in very mild traumatic brain injuries at secondary school level. Statistically significant (p<=0.05)results of the SAC test totals between both the vMTBI and MTBI groups were documented in the different games throughout the rugby season and compared with the baseline test. No statistically significant differences (p<=0.05) between the pre-season and post-season's scores of the SAC test totals were documented. A decrease in academic performance in the subject Afrikaans (year 1 compared with year 2) with a p-value of p=O.O17(group 1) and p=O.O16(group 2) respectively was found. Conclusion - The findings of this study indicate a high incidence of vMTBI in a cohort of secondary school rugby players in one season, a statistically significant reduction (p=O.O1 )in delayed memory of the vMTBI rugby players and a statistically significant decrease in academic performance p=O.O17 (group 1) and p=O.O16 (group 2) in the subject Afrikaans from year 1 to year 2 final examinations. / Thesis (Ph.D. (Human Movement Science))--North-West University, Potchefstroom Campus, 2006.

Children with traumatic brain injury (TBI) often experience difficulties with inhibitory control (IC), manifest in both neurocognitive function (poor performance on the stop signal task, SST) and behavior (emergence of de novo attention-deficit/hyperactivity disorder, or secondary ADHD, S-ADHD). IC allows for the regulation of thought and action, and interacts with reward to modify behaviour adaptively as environments change. Children with developmental or primary ADHD (P-ADHD) exhibit poor IC and abnormalities when responding to rewards, yet the extent to which S-ADHD is similar to and different from P-ADHD in terms of these behaviours is not well-characterized. The cancellation and restraint versions of the SST were used to examine the effects of rewards on 2 distinct forms of IC in children and adolescents divided into 4 groups (control, TBI, S-ADHD, and P-ADHD). The SST requires participants to respond to a “go signal” and inhibit their responses when encountering a “stop signal”. Rewards improved performance similarly across groups, ages, and cancellation and restraint IC tasks. Adolescents exhibited better IC and faster and less variable response execution relative to children. Significant IC deficits were found in both tasks in the P-ADHD group, with participants with S-ADHD exhibiting intermediate cancellation performance relative to the other groups. Participants with TBI without S-ADHD were not impaired on either task. The relationship between neurocognitive and behavioral IC was examined by comparing multi-informant ratings of IC across groups, and examining the relationship between ratings and IC performance on the SST. Participants in the control and TBI groups were rated within the typical range, and exhibited fewer problems than either of the ADHD groups, who differed from each other (the P-ADHD group was rated as more inattentive than the S-ADHD group). Moderate to high concordance was found between parent and teacher reports, each of which was poorly concordant with self-reports. The P-ADHD and S-ADHD groups were unaware of their own deficits. Poorer IC predicted parent and teacher classification of participants into ADHD subtypes, although IC did not predict rating concordance. Despite similar clinical presentations, S-ADHD and P-ADHD differ in the phenotypic expression of behaviour and manifestation of IC across contexts.

No description available.

Traumatic brain injury (TBI) is a relatively unknown disease considering the tens of millions of people affected around the world each year. Many TBI patients die from their injuries and survivors often suffer from life-long disabilities. The primary injury initiates a variety of cellular and molecular processes that are both beneficial and detrimental for the brain, but that are not fully understood. The focus of this thesis has been to study the role of astrocytes in clearance of dead cells after TBI and to identify injury specific proteins that may function as biomarkers, by using cell cultures, animal models and in cerebrospinal fluid (CSF) from TBI patients. The result demonstrates a new function in that astrocytes, the most numerous cell type in the brain, engulf dead cells after injury both in cell cultures and in adult mice and thereby save neurons from contact-induced apoptosis. Astrocytes are effective phagocytes, but degrade the ingested dead cells very slowly. Moreover, astrocytes express the lysosome-alkalizing proteins Rab27a and Nox2 as well as major histocompatibility complex class II, the receptors on which antigens are being presented. By lowering the pH of the lysosomes with acidic nanoparticles, the degradation increases, but the astrocytes still remained less effective than macrophages. Taken together, the data indicates that the low acidification in astrocytes can preserve antigens and that astrocytes may be able to activate T cells. The expression and secretion of injury-specific proteins was studied in a cell culture model of TBI by separate mass spectrometry analysis of cells and medium. Interestingly, close to 30 % of the injury-specific proteins in medium are linked to actin, for example ezrin of the ezrin/radixin/moesin (ERM) protein family. Ezrin, but none of the other ERM proteins or actin, is actively secreted after injury. Extracellular ezrin also increases in CSF in response to experimental TBI in rats and is present in CSF from TBI patients, indicating that ezrin is a potential biomarker for TBI.

No description available.

Introduction: Mild traumatic brain injury (mTBI) accounts for the vast majority of all paediatric TBI cases. It is an important public health concern, yet the long-term psychiatric and behavioural outcomes remain imperfectly understood. Aim. This study aims to examine the association between paediatric mTBI and psychiatric and offending outcomes in adulthood, while considering the impact of sex, age at injury and duration since injury on outcome. Participants: Participants with mTBI (n=57) were compared to those with moderate/severe TBI (n=62) and to orthopaedic injury controls (n=42). All participants were injured at age 17 or younger and were 18 years or older at the time of assessment. Outcome measures: Based on the DSM-IV-TR criteria, structured interviews were used to assess participants’ experience of symptoms consistent with major depressive disorder, anxiety disorders (including generalised anxiety disorder, panic attacks and panic disorder, agoraphobia, social phobia, post-traumatic stress disorder, and specific phobia), and substance abuse and/or dependence. Participants’ were asked to report on their lifetime involvement with offending, arrests, and diversions and/or convictions. Results: At age 18-31, participants with a paediatric mTBI were significantly more likely than orthopaedic injury controls to endorse symptoms consistent with major depressive disorder by 3.17 times, anxiety disorders by 5.81 times, and internalising disorders in general by 5.80 times and the risk in the mTBI group was greater than that for those with moderate/severe TBI. Females with mTBI were significantly more likely than males, by five times, to endorse an internalising disorder. Paediatric mTBI was not significantly associated with externalising problems when compared with controls; however, males with mTBI were 6.57 times more likely to endorse externalising behaviours than females. Conclusions: Paediatric mTBI is a risk factor for internalising disorders in adulthood, particularly for females. Such findings have implications for assessment and treatment of problems associated with paediatric mTBI.

The α7 nicotinic acetylcholine receptor (nAChR) is involved in learning and memory, synaptic plasticity, neuroprotection, inflammation, and presynaptic regulation of neurotransmitter release. Alzheimer’s disease (AD), a neurodegenerative disease characterized by diminished cognitive abilities, memory loss, and neuropsychiatric disturbances, is associated with a loss of nAChRs. Similarly, traumatic brain injury (TBI) may result in long term neurobehavioral changes exemplified by cognitive dysfunction. Deficits in α7 nAChR expression have previously been shown in experimental TBI and may be related to cognitive impairment experienced in patients following TBI. The purpose of this dissertation was to investigate changes in α7 nAChR expression in models of neurodegeneration and determine if allosteric modulation of the nAChR facilitates functional recovery following experimental TBI through changes in nAChRs. Experimental models employed include a transgenic mouse model of AD that overexpresses the amyloid precursor protein (APPswe mice) and the controlled cortical impact injury model of TBI in rats. Quantitative receptor autoradiography using α-[125I]-bungarotoxin and [125I]-epibatidine and in situ hybridization were used to investigate changes in nAChR density and mRNA expression, respectively. In the first study, the effects of aging and β-amyloid on α7 nAChR expression were evaluated in APPswe mice. Hippocampal α7 nAChR density was significantly upregulated in APPswe mice compared to wild-type mice. It is postulated that elevated Aβ levels bind to the α7 nAChR resulting in upregulation. In a second study, galantamine, a medication used in the treatment of AD, was administered subchronically following experimental TBI to determine if treatment could facilitate cognitive recovery and affect nAChR expression. Interestingly, the results indicate TBI interferes with agonist mediated upregulation of nAChRs, and galantamine did not improve function in a behavioral task of learning a memory. In a third study, the regulation of TBI related deficits in α7 nAChRs was examined 48 hours following injury. α7 nAChR deficits occurred with a reduction in α7 mRNA in several hippocampal regions and non-α7 nAChR deficits occurred with a reduction in α4 mRNA in the metathalamus. The results of these studies suggest AD and TBI may involve complex but parallel processes contributing to the regulation of α7 nAChRs.

Posttraumatic epilepsy is a common consequence of brain trauma. However, little is known about how long-term changes in local excitatory and inhibitory synaptic networks contribute to epilepsy after closed-head brain injury. This study adapted a widely used model of experimental brain injury as a mouse model of posttraumatic epilepsy. Behavioral seizure activity and alterations in synaptic circuitry in the dentate gyrus were examined in mice after experimental cortical contusion brain injury. Spontaneous behavioral seizures were observed in 20% of mice after moderate injury and 36-40% of mice weeks after severe injury. In the dentate gyrus, most mice displayed regionally localized mossy fiber reorganization ipsilateral to the injury that was absent in control mice or sections contralateral to the injury. Extracellular field and whole-cell patch clamp recordings were performed in acute brain slice preparations of the dentate gyrus. Dentate granule cells displayed spontaneous and evoked activity that was consistent with network synchronization and the formation of recurrent excitatory network only in slices that had posttraumatic mossy fiber sprouting. The excitability of surviving hilar GABAergic interneurons, which provide important feedback inhibition to granule cells, was examined at similar time points. Cell-attached and whole-cell voltage-clamp recordings revealed increased spontaneous and glutamate photostimulation-evoked excitatory input to hilar GABA neurons ipsilateral to the injury, versus control and contralateral slices. Despite increased excitatory synaptic input to interneurons, whole-cell voltage-clamp recordings revealed a reduction in inhibitory synaptic input to granule cells. These findings suggest that there are alterations in excitatory and inhibitory circuits in mice with posttraumatic mossy fiber sprouting and seizures after cortical contusion head injury.

The development of Parkinson's disease (PD) in humans has been linked to genetic and environmental factors for many years. However, finding common single insults which can produce pathology in humans has proved difficult. Exposure to trichloroethylene (TCE) or traumatic brain injury (TBI) has been shown to be linked to PD and it has also been proposed that multiple insults may be needed for disease development. The present studies show that exposure to TCE prior to a TBI can result in pathology similar to early PD and that the interaction of both insults is required for impairment in behavioral function, and cell loss. Following exposure to TCE for 2 weeks there is a 75% impairment in mitochondrial function but it has yet to be shown if the addition of a TBI can make this worse. If the exposure to TCE is reduced to 1 week and combined with TBI a 50% reduction in mitochondrial function is observed following the dual injury which requires both insults. These studies provide further support for the hypothesis that PD may result from a multifactorial mechanism. It had been established that regional differences exist in mitochondrial function across brain regions. The present studies indicate that previous findings are not likely to be the result of differences in individual mitochondria isolated from the cortex, striatum, and hippocampus. Further analysis of the effect of mitochondrial inhibitors on enzyme activity and oxygen consumption reveal that the different regions of the brain are similarly affected by the inhibitors. These results suggest that findings from previous studies indicating regionally specific deficits following systemic toxin exposure, such as with TCE, are not the result of regional differences in the individual mitochondria. Given that TBI results in significant dysfunction, finding effective therapeutics for TBI will provide substantial benefits to individuals suffering an insult. Treatment with Pioglitazone following TBI reduced mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation. These findings provide initial evidence that treatment with Pioglitazone may be an effective intervention for TBI.