Brain injury is a serious clinical problem. The success of recovery from brain injury involves functional compensation in the affected brain area. We are interested in general mechanisms that underlie compensatory plasticity after brain damage, particularly when multiple brain areas or multiple modalities are included. In this thesis, I studied the function of auditory cortex after recovery from neonatal midbrain damage as a model system that resembles patients with brain damage or sensory dysfunction. I addressed maladaptive changes of auditory cortex after invasion by ectopic visual inputs. I found that auditory cortex contained auditory, visual, and multisensory neurons after it recovered from neonatal midbrain damage (Mao et al. 2011). The distribution of these different neuronal responses did not show any clustering or segregation. As might be predicted from the fact that auditory neurons and visual neurons were intermingled throughout the entire auditory cortex, I found that residual auditory tuning and tonotopy in the rewired auditory cortex were compromised. Auditory tuning curves were broader and tonotopic maps were disrupted in the experimental animals. Because lateral inhibition is proposed to contribute to refinement of sensory maps and tuning of receptive fields, I tested whether loss of inhibition is responsible for the compromised auditory function in my experimental animals. I found an increase rather than a decrease of inhibition in the rewired auditory cortex, suggesting that broader tuning curves in the experimental animals are not caused by loss of lateral inhibition. These results suggest that compensatory plasticity can be maladaptive and thus impair the recovery of the original sensory cortical function. The reorganization of brain areas after recovery from brain damage may require stronger inhibition in order to process multiple sensory modalities simultaneously. These findings provide insight into compensatory plasticity after sensory dysfunction and brain damage and new information about the role of inhibition in cross-modal plasticity. This study can guide further research on design of therapeutic strategies to encourage adaptive changes and discourage maladaptive changes after brain damage, sensory/motor dysfunction, and deafferentation.

Purpose: Traumatic brain injury (TBI) leads to important and deleterious neuroinflammation, as evidenced by edema, cytokine production, induction of nitric oxide synthase, and leukocyte infiltration. Strategies that block inflammatory and oxidative mediators have been shown to induce neuroprotective and anti-inflammatory effects after brain injury. After TBI, cerebral vascular endothelial cells play a crucial role in the pathogenesis of inflammation. In this study, we hypothesized that cerebral vascular endothelial cells play a crucial role in the pathogenesis of inflammation after TBI and, in conjunction with leukocytes, represent a key cellular target for statin therapy. We investigated the effect of acute and continuous treatment of simvastatin on behavior and inflammation in adult rats following experimental TBI. Materials and Methods: Cortical contusions were induced using a device adapted from the impact method. There were 3 groups: (1) sham group, craniotomy only; (2) control group, TBI without treatment; and (3) treatment group, TBI with simvastatin administration. The treatment group received 15 mg/kg of simvastatin daily for 3 days. Neurological function was assessed with the grip test (Grip strength meter, Singa). Results: Non-treatment control group had a significantly greater increase in ICAM-1 expression from pre-injury to the post-injury 72 h time point, compared to the simvastatin treatment group. The treatment group had a significantly smaller amount of reduction in successful trials in grip test than the control group did from baseline to 72 h. The analysis of western blot and pathological study also demonstrated similar results. Conclusion: Our findings indicate that continuous administration of simvastatin after injury attenuates the cerebral vascular endothelial inflammatory response and improves functional and histological outcomes in a rat model of TBI. This improvement is associated with a reduction in expression of ICAM-1 in the blood and brain after rat TBI when compared with the untreated control group. Hence, we recommend simvastatin administration in the first 72 h following TBI.

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.

Biomarker research is of great interest in the field of traumatic brain injury (TBI), since there are numerous potential markers that may indicate central nervous system damage, yet the brain is normally well isolated and discovery is at its infancy. Traditional methods for biomarker discovery include time consuming multi step chromatographic mass spectrometery (MS) techniques or pre-defined serial probing using traditional assays, making the identification of biomarker panels limiting and expensive. These shortfalls have motivated the development of a MS based probe that can be embedded into 3D neural cultures and obtain temporal and spatial information about the release of biomarkers. Using the high sensitivity MS ionization method of nano-electrospray ionization (nano-ESI) with an in-line microdialysis (MD) unit allows us to use MS to analyze low concentrations of TBI biomarkers from within cell cultures with no need for off-line sample manipulation. This thesis goes through the development of the probe by studying the theoretical principles, simulations and experimental results of the probe's capability to sample small local concentrations of a marker within cell culture matrix, the MD unit's sample manipulation capabilities, and the ability to detect markers using in-line MD-nano-ESI MS.

Fragestellung: Gegenstand dieser Untersuchung ist der diagnostische Nutzen der Neuro-Biomarker S100B-Protein und Neuronenspezifische Enolase (NSE) bei leichten Schädel-Hirn-Verletzungen im Kindesalter. Es wird untersucht, ob anhand der posttraumatischen S100B- und NSE-Serum-Konzentrationen Kinder mit einer Schädelprellung und einem leichten Schädel-Hirn-Trauma (SHT) differenziert werden können. Material und Methode: In einer prospektiven, klinischen Studie werden die posttraumatischen S100B- und NSE-Serum-Konzentrationen von Kindern im Alter zwischen 6 Monaten und 15 Jahren mit einer Schädelprellung oder einem leichten SHT untersucht. Kinder mit extrakraniellen Begleitverletzungen und Begleiterkrankungen sind ausgeschlossen. Die Blutentnahme erfolgt innerhalb von 6 Stunden nach dem Trauma. Es werden 2 diagnostische Gruppen definiert: Gruppe 1: asymptomatische Schädelprellungen (Glasgow-Coma-Scale [GCS] 15 Punkte), Gruppe 2: leichte SHT (GCS 13-15 Punkte) mit klinischen Zeichen einer Gehirnerschütterung (kurze Bewusstlosigkeit, Amnesie, Übelkeit, Erbrechen, Somnolenz, Kopfschmerzen, Schwindel, Sehstörungen, Kreislaufreaktion). Die S100B- und NSE- Konzentrationen werden zwischen beiden Diagnosegruppen verglichen. Die Korrelation zwischen S100B und NSE sowie zwischen den Markern und dem Alter der Kinder, dem Zeitraum zwischen Trauma und Blutentnahme, dem GCS-Wert und dem Vorhandensein von Kopfplatzwunden wird analysiert. Ergebnisse: 148 Kinder sind in die Studie eingeschlossen (53 Kinder mit einer Schädelprellung und 95 mit einem leichten SHT). Nach Adjustierung der gemessenen Marker-Konzentrationen auf Unterschiede im Alter und Zeitraum zwischen Trauma und Blutentnahme unterscheiden sich die S100B- und NSE-Konzentrationen nicht signifikant zwischen Kindern mit einer Schädelprellung und einem leichten SHT. Zwischen den S100B- und NSE-Konzentrationen besteht eine signifikant positive Korrelation. Beide Marker korrelieren signifikant negativ mit dem Alter und dem Entnahmezeitraum. Der GCS-Wert und das Vorhandensein von Kopfplatzwunden zeigen keinen Effekt auf die Marker-Konzentrationen. Schlussfolgerung: Die posttraumatischen S100B- und NSE-Serum-Konzentrationen zeigen keinen diagnostischen Nutzen bei der Differenzierung zwischen Kindern mit einer Schädelprellung und Kindern mit einem leichten SHT. S100B und NSE sind altersabhängige Marker.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2010. / Härtill 3 uppsatser. På spikbladet med titel : Inflammation in experimental neonatal brain injury and in a clinical study of preterm birth : involvement of galectin-3 and free radical formation.

This study examined the effects of a smoking cessation program using vouchers as reinforcers with individuals with traumatic brain injury and a history of substance abuse. The intervention was conducted at a residential facility that houses individuals with Traumatic Brain Injury (TBI). Vouchers were delivered contingent on reductions of carbon monoxide (CO) samples of 5 ppm or less across a shaping phase, and an abstinence induction phase. A standard pay phase was added at the end of the study to examine the effects of a standardized reinforcement scale with the abstinence criterion set at 8 ppm or less. Reductions in CO were not robust in the shaping and abstinence induction phase. The standard pay schedule showed some improvements in CO levels with less variability for two of the three participants.

Falls among the elderly population continue to be a growing concern in the healthcare industry and are marked by staggeringly high social and economic costs. The incidence of falls is known to increase with age, and currently the elderly population is growing at an astounding rate as baby-boomers are now entering this age group. Also, recovery following fall-related injuries decreases with increased age. These confounding factors currently make falls a very important area of research. Of the injuries typically seen in falls among the elderly, head injuries are one of the most debilitating. Death due to head trauma among the elderly is gaining national attention; head trauma is now considered the number one cause of death among elders who fall1. Among other technologies, medical helmets are often employed to protect against such injuries, but patient compliance with these helmets remains an issue. Current helmets use foams and cotton as padding, contributing to clumsy designs. Dilatent and honeycomb materials may be the future of this industry as their low weight and high efficacy per thickness make them ideal materials for thinner, lighter, less cumbersome head protection devices. This study outlines various modes of head injury and then highlights several head protection measures. The newer materials are tested using various methods to determine the most promising candidates for prototype designs. Next, three prototypes are assembled from the newer materials and compared directly based on the protection measures established. Finally, the top-performing prototype is compared against two existing medical helmets in a similar fashion. The results show that the best prototype significantly outperforms one of the existing medical helmets, and shows slight improvement over the other. These results establish the promise of these newer materials in the application of head protection devices.

Traumatic brain and spinal cord injury continue to be substantial clinical problems with few available treatment strategies. Individuals who are at a greater risk for sustaining a central nervous system (CNS) injury, such as professional athletes and military personnel, may benefit from a prophylactic supplement that would intervene in the neurodegenerative pathways immediately following injury. The high demand for selenium within the central nervous system, as well as the synthesis of selenoproteins by neurons and astrocytes suggests a critical role of selenium within the brain and spinal cord. Studies were designed to test the efficacy of enriched dietary selenium status in providing neuroprotective benefits in rodent models of spinal cord and traumatic brain injury. Levels of selenium storage within the CNS are increased relative to the amount of selenium present in the diet, indicating that selenium compounds effectively cross the blood brain barrier. In a model of moderate severity spinal cord contusion injury, dietary selenium supplementation reduced the number of days until recovery of independent bladder function following injury. These benefits did not translate to improvements in locomotor function during open field testing or reduction in overall lesion volume in the injured animal groups. Examination of gene expression changes 24 hours after spinal cord injury revealed that dietary selenium enrichment increased expression of genes involved in DNA repair, mitochondrial respiration, and transcriptional regulation. By expanding the scope of these studies to include models of traumatic brain injury, these data show the importance of selenium in the cortex as well. In particular, when compared to diets deficient in selenium, higher levels of dietary selenium improve spatial memory performance and mitochondrial respiration. The results of this dietary study show modest improvements following both traumatic brain and spinal cord injury and suggest that while selenium enrichment may not have a profound effect on the secondary injury cascade immediately following injury, the presence of adequate dietary selenium is critical for mitochondrial respiration. Together the results of these studies suggest that dietary supplementation may play a subtle role in injury mechanisms within the CNS and warrant further investigation.

<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