Traumatic brain injury (TBI) has a 20% mortality rate and a 10-15% rate of resultant permanent disability. The consequences of TBI range from brief loss of consciousness, to prolonged coma or death. Mild TBI is amongst the common causes of admission to trauma centers all over the world. Future technologies such as magnetic resonance elastography and robotic surgery demand information about the physical properties of brain tissue. Walsh and Schettini described the mechanical behavior of brain tissue under normal status as nonlinear viscoelastic behavior and defined the associated biomechanical changes and responses in a quantitative measurement of the material changes. Yet, there is still a lack of data concerning time-dependent deformation and mechanical property changes associated with TBI. My goal in this project was to describe these mechanical responses and to create a system for measuring and evaluating the mechanical response of brain tissue in vivo. This was to be achieved by inducing cortical contusions with a calibrated weight-drop method in seventy-four young adult male Sprague-Dawley rats. Instrumented indentation was performed on control brains and 1 hour to 3 weeks after contusion with intact dura using a 4-mm-diameter flat punch indenter to a maximum depth of 1.2 mm at loading. Loading rates did not exceed 0.34 N/min and 1.2 mm/min. In order to obtain force displacement data, we studied the elastic response of the traumatized brain tissue and the deformation process (creep) during the loading and unloading of indenter. After euthanasia, the brain was removed and evaluated histologically with different methods to reveal acute and chronic changes related to the contusion. The results revealed that the biomechanical properties of the brain tissue were changed after cortical contusion. Brain tissue elasticity decreased in the edematous brain at one day following the contusion and increased at 3 weeks, in association with reactive astroglial changes. This experimental technique, combined with mathematical modeling, might eventually lead to a better understanding of the physical changes in brain following TBI.

Traumatic brain injury (TBI) has a 20% mortality rate and a 10-15% rate of resultant permanent disability. The consequences of TBI range from brief loss of consciousness, to prolonged coma or death. Mild TBI is amongst the common causes of admission to trauma centers all over the world. Future technologies such as magnetic resonance elastography and robotic surgery demand information about the physical properties of brain tissue. Walsh and Schettini described the mechanical behavior of brain tissue under normal status as nonlinear viscoelastic behavior and defined the associated biomechanical changes and responses in a quantitative measurement of the material changes. Yet, there is still a lack of data concerning time-dependent deformation and mechanical property changes associated with TBI. My goal in this project was to describe these mechanical responses and to create a system for measuring and evaluating the mechanical response of brain tissue in vivo. This was to be achieved by inducing cortical contusions with a calibrated weight-drop method in seventy-four young adult male Sprague-Dawley rats. Instrumented indentation was performed on control brains and 1 hour to 3 weeks after contusion with intact dura using a 4-mm-diameter flat punch indenter to a maximum depth of 1.2 mm at loading. Loading rates did not exceed 0.34 N/min and 1.2 mm/min. In order to obtain force displacement data, we studied the elastic response of the traumatized brain tissue and the deformation process (creep) during the loading and unloading of indenter. After euthanasia, the brain was removed and evaluated histologically with different methods to reveal acute and chronic changes related to the contusion. The results revealed that the biomechanical properties of the brain tissue were changed after cortical contusion. Brain tissue elasticity decreased in the edematous brain at one day following the contusion and increased at 3 weeks, in association with reactive astroglial changes. This experimental technique, combined with mathematical modeling, might eventually lead to a better understanding of the physical changes in brain following TBI.

Subconcussive (SC) impacts have become a growing concern within the neuroscience community regarding the immediate and long-lasting effects of sports-related injuries. While a single low-level impact, i.e., a subconcussion, may not cause cerebral perturbations, it has been increasingly recognized that repeated SC exposure can induce deleterious effects. Therefore, determining the lower limits of systematic perturbation resulting from multiple SC impacts is of critical importance in expanding our understanding of cerebral vulnerability and recovery. Currently, there is a lack of correlation between a mild traumatic brain injury (mTBI) and repeated SC impacts with respect to injury biomechanics. Moreover, the cumulative threshold for repetitive low-level impacts is currently undefined. Thus, this research was designed to determine the pathophysiological differences between a single impact of an mTBI and repeated SC impacts with a subdivided cumulative kinetic energy of the single mTBI impact. In order to address this gap in knowledge, the present investigation employed a surgery-free, closed-head, weight drop injury device capable of producing repeatable, head impacts within a rat model. General locomotion and anxiety-like behavior were assessed using an Open Field Test and motor coordination dysfunction was measured using the rotarod assay. Neuroinflammation was measured using immunohistochemical assessment of astrogliosis (GFAP) and microgliosis (Iba-1) within the hippocampus. Additionally, immunohistochemical assessment of neuronal loss (NeuN) was measured within the hippocampus. To investigate the tolerance and the persistence of cerebral vulnerability following a single mTBI and repeated subconcussive impacts, measurement outcomes were assessed over two-time points (3- and 7-days) post final impact. Although injury groups were not statistically different from their associated sham groups with respect to behavioral outcomes; on average, RSC injury rats displayed a significant increase in anxious-like behavior after 7-days of recovery compared to the single mTBI group. From an inflammatory perspective, both mTBI and RSC injury groups led to extensive microgliosis in the gray matter following 3-days post-impact. Overall, this work’s findings do not provide evidence in support of the notion that repeated subconcussive impacts do result in behavioral disturbances and neuroinflammation, that do not manifest following a single mTBI of the same energy input.

<p>Traumatic brain injury (TBI) is a leading cause of death and disability TBI survivors often suffer from severe disturbances of cognition, memory and emotions. Improving the treatment is of great importance, but as of yet no specific neuroprotective treatment has been found. After TBI there are changes in ion homeostasis and protein regulation, causing generation of reactive oxygen species (ROS). Overproduction of ROS can lead to damage cellmembranes, proteins and DNA and secondary cell death. In the present thesis experimental TBI in rats were used to study the effects of the ROS scavengers α-phenyl-N-tert-butyl-nitrone (PBN) and 2-sulfophenyl-N-tert-butyl-nitrone (S-PBN) on morphology, function, intracellular signalling and apoptosis. </p><p>Posttreatment with PBN and S-PBN resulted in attenuation of tissue loss after TBI and S-PBN improved cognitive function evaluated in the Morris water maze (MWM). Pretreatment with PBN protected hippocampal morphology, which correlated to better MWM-performance after TBI.</p><p>To detect ROS-generation in vivo, a method using 4-hydroxybenzoic acid (4-HBA) microdialysis in the injured cortex was refined. 4-HBA reacts with ROS to form 3,4-DHBA, which can be quantified using HPLC, revealing that ROS-formation was increased for 90 minutes after TBI. It was possible to attenuate the formation significantly with PBN and S-PBN treatment. </p><p>The activation of extracellular signal-regulated kinase (ERK) is generally considered beneficial for cell survival. However, persistent ERK activation was found in the injured cortex after TBI, coinciding with apoptosis-like cell death 24 h after injury. Pretreatment with the MEK-inhibitor U0126 and S-PBN significantly decreased ERK activation and reduced apoptosis-like cell death. Posttreatment with U0126 or S-PBN showed robust protection of cortical tissue.</p><p>To conclude: ROS-mediated mechanisms play an important role in secondary cell death following TBI. The observed effects of ROS in intracellular signalling may be important for defining new targets for neuroprotective intervention.</p>

Traumatic brain injury (TBI) is a leading cause of death and disability TBI survivors often suffer from severe disturbances of cognition, memory and emotions. Improving the treatment is of great importance, but as of yet no specific neuroprotective treatment has been found. After TBI there are changes in ion homeostasis and protein regulation, causing generation of reactive oxygen species (ROS). Overproduction of ROS can lead to damage cellmembranes, proteins and DNA and secondary cell death. In the present thesis experimental TBI in rats were used to study the effects of the ROS scavengers α-phenyl-N-tert-butyl-nitrone (PBN) and 2-sulfophenyl-N-tert-butyl-nitrone (S-PBN) on morphology, function, intracellular signalling and apoptosis. Posttreatment with PBN and S-PBN resulted in attenuation of tissue loss after TBI and S-PBN improved cognitive function evaluated in the Morris water maze (MWM). Pretreatment with PBN protected hippocampal morphology, which correlated to better MWM-performance after TBI. To detect ROS-generation in vivo, a method using 4-hydroxybenzoic acid (4-HBA) microdialysis in the injured cortex was refined. 4-HBA reacts with ROS to form 3,4-DHBA, which can be quantified using HPLC, revealing that ROS-formation was increased for 90 minutes after TBI. It was possible to attenuate the formation significantly with PBN and S-PBN treatment. The activation of extracellular signal-regulated kinase (ERK) is generally considered beneficial for cell survival. However, persistent ERK activation was found in the injured cortex after TBI, coinciding with apoptosis-like cell death 24 h after injury. Pretreatment with the MEK-inhibitor U0126 and S-PBN significantly decreased ERK activation and reduced apoptosis-like cell death. Posttreatment with U0126 or S-PBN showed robust protection of cortical tissue. To conclude: ROS-mediated mechanisms play an important role in secondary cell death following TBI. The observed effects of ROS in intracellular signalling may be important for defining new targets for neuroprotective intervention.