Traumatic Brain Injury (TBI) and its resulting pathophysiology have been extensively examined before. However, little is known in the area of pre-injury factors that influence vulnerability to and recovery from TBI. The current study examined the effects of pre-injury chronic nicotine exposure on Morris water maze performance, following TBI in adolescent rats. Fifteen days prior to lateral fluid percussion injury (FPI), adolescent rats (30 days old) were implanted with osmotic mini-pumps filled with nicotine (4.5mg/kg/day) or saline. Half the rats received lateral fluid percussion injury and half received sham injury. Animals were assessed for cognitive recovery in the Morris water maze on post-injury days (PID) 11 through 15. The MWM results indicated no significant differences between injured animals infused with chronic nicotine and injured animals infused with saline.

The overall goal of this research is to develop methods and algorithms to investigate the severity of Traumatic brain injury (TBI) and to estimate the intracranial pressure (ICP) level non-invasively. Brain x-ray computed tomography (CT) images and artificial intelligence methods are employed to estimate the level of ICP. Fully anisotropic complex wavelet transform features are proposed to extract directional textural features from brain images. Different feature selection and classification methods are tested to find the optimal feature vector and estimate the ICP using support vector regression. By using systematic feature extraction, selection and classification, promising results on ICP estimation are achieved. The results also indicate the reliability of the proposed algorithm. In the following, case-based finite element (FE) models are extracted from CT images using Matlab, Solidworks, and Ansys software tools. The ICP estimation obtained from image analysis is used as an input to the FE modeling to obtain stress/strain distribution over the tissue. Three in-plane modeling approaches are proposed to investigate the effect of ICP elevation on brain tissue stress/strain distribution. Moreover, the effect of intracranial bleeding on ICP elevation is studied in 2-D modeling. A mathematical relationship between the intracranial pressure and the maximum strain/stress over the brain tissue is obtained using linear regression method. In the following, a 3-D model is constructed using 3 slices of brain CT images. The effect of increased ICP on the tissue deformation is studied. The results show the proposed framework can accurately simulate the injury and provides an accurate ICP estimation non-invasively. The results from this study may be used as a base for developing a non-invasive procedure for evaluating ICP using FE methods.

Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion, with approximately 3.6 million sports related concussions occurring yearly in the United States alone (Bailes, 2015, Azad et al., 2015). An MTBI is an acute brain injury resulting from mechanical energy to the head from external forces (Bailes 2015). Symptoms of an MTBI include visual disturbances, dizziness, nausea and vomiting, light sensitivity, loss of balance, and a general feeling of fatigue (Bailes 2015). MTBI’s are first diagnosed through changes in ImPACT baseline scores as well as Vestibular Ocular Motor Screening (Mucha et al., 2014). Repetitive MTBI and/or repetitive sub-concussive head trauma have been tentatively linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE) (Gardner et al., 2015). The major limitation of the link between MTBI and CTE is that CTE can only be diagnosed post-mortem (Azad et al., 2015). Due to that limitation, the prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear (Gardner et al., 2015). Newer methods of research including SNTF immunostaining and L-COSY are being further developed and studied to better diagnose MTBI and its link to CTE by exploring changes in brain protein formation and brain neurochemistry (Johnson et al., 2015, Lin et al., 2015). Through research development and case studies on professional American football players and boxers, a link between MTBI, particularly repetitive MTBI and CTE has been formed (Maroon et al., 2014).

Postmortem brains from young athletes with a history of repetitive concussive head injury and military service personnel with history of blast neurotrauma revealed evidence of parenchymal contusion, myelinated axonopathy, microvasculopathy, neuroinflammation, neurodegeneration, and phosphorylated tauopathy consistent with chronic traumatic encephalopathy (CTE) (L. E. Goldstein et al., 2012). The mechanisms by which head trauma induces acute concussion and chronic sequelae are unknown. To elucidate the mechanistic connection between traumatic brain injury (TBI), acute concussion and chronic sequelae, including CTE, require the use of animal models. This doctoral dissertation investigated the hypothesis that closed-head impact injury in mice triggers acute neurological signs associated with sport-related concussion as well as brain pathologies and functional sequelae associated with CTE. To test this hypothesis, we developed a mouse model of impact neurotrauma that utilizes a momentum transfer device to induce non-skull deforming head acceleration, triggering transient neurological signs consistent with acute concussion and traumatic brain injury (TBI) in unanesthetized C57BL/6 mice. The Boston University Concussion Scale (BUCS) was developed to assess neurological signs that are consistent with acute concussion in humans. Mice exhibited contralateral circling and limb weakness, locomotor abnormalities, and impaired gait and balance that recapitulate acute concussion in humans. Concussed mice recovered neurological function within three hours, but demonstrated persistent myelinated axonopathy, microvasculopathy, neuroinflammation, and phosphorylated tauopathy consistent with early CTE. Concussive impact injury also induced blood-brain barrier disruption, neuroinflammation (including infiltration peripheral monocytes and activation microglia), impaired hippocampal axonal conduction, and defective long-term potentiation (LTP) of synaptic transmission in medial prefrontal cortex. Kinematic analysis during impact injury revealed head acceleration of sufficient intensity to induce acute concussion, traumatic brain injury (TBI), early CTE-linked pathology, and related chronic sequelae. Surprisingly, the presence or degree of concussion measured by BUCS did not correlate with brain injury. Moreover, concussion was observed following impact injury but not blast exposure under conditions that induce comparable head kinematics. Empirical pressure measurements and dynamic modeling revealed greater pressure on the head and compression wave loading in the brain during impact compared to blast neurotrauma. These findings suggest acute concussion is triggered by focal loading of energy that transit the brain before onset of macroscopic head motion. By contrast, the forces associated with rapid head motion is sufficient to induce CTE-linked pathology. Our results indicate that while acute concussion and chronic sequelae may be triggered by the same insult, the pathophysiological responses underpinning these effects are engaged through distinct mechanisms and time domains. Our results indicate that concussion is neither necessary nor sufficient to induce acute brain injury or chronic sequelae, including CTE. / 2018-02-17T00:00:00Z

Our murine model of mild traumatic brain injury (mTBI) has shown improved survival after Pseudomonas aeruginosa (Psd) challenge as compared to controls (tail trauma or sham injury). Previous work suggests an mTBI-specific involvement of the neuro-immune axis which augments the innate immune response, increasing survival. Additional factors for the enhanced mTBI survival were explored via microarray analysis of lungs harvested 48 hours post-trauma, the point prior to Psd challenge in our model. At 48 hours post-trauma, mTBI lungs have a number of upregulated ATP synthesis and mitochondrial gene sets. Increased available energy could prime the mTBI lungs, allowing an earlier and more robust response to Psd infection, possibly contributing to the increased mTBI survival. This is supported by increased neutrophil recruitment in the bronchoalveolar lavage of mTBI mice four hours after Psd instillation. Downregulated gene sets related to cellular connections suggest that neutrophils recruited to the lung have an easier extravasation pathway into the air space of mTBI lungs compared to control. Based on genetic and neutrophil recruitment data, it is possible that mTBI creates an energetically prepared and easily accessible lung better tailored for recruiting and allowing entry of neutrophils in response to an infection compared to control.

The State of Kentucky has a high and increasing number of reported cases of traumatic brain injury (TBI), mostly attributed to motor vehicle crashes, falls, and being struck by or against an object. Young adults are among those most at-risk for experiencing a TBI through motor vehicle crashes. Using existing data from the Kentucky Post-School Outcomes Center (KyPSO), 90 youth with TBI were identified within a period of 6-years of the longitudinal study (2012-2017). The majority were males and White. Descriptive statistics, chi square, and logistic regression were used to examine the post-secondary outcomes for youth with TBI, using four demographic variables: gender, ethnicity, residence, and rural or urban status. None of these were associated with post-secondary outcomes for the sample. The results indicated that more than 50% of the youth with TBI had positive outcomes, yet they rarely used the services provided for them in the schools or at the workplace. This study suggests that, although the demographic characteristics did not predict post-secondary outcomes, other variables within education and employment yielded interesting results that could benefit rehabilitation counselors.

In the United States, 2.8 million people suffer a traumatic brain injury (TBI) annually. Between 25%-50% of TBI injuries happen under alcohol intoxication. It is not understood how alcohol impacts patient outcomes via secondary injury pathways. Secondary injury pathways offer a window for therapeutic interventions, but there has been little success finding effective medications. Slice cultures offer a way to study secondary injury mechanisms in a controlled manner. The transection injury can model excitotoxicy seen following TBI. The current studies examined the effect of alcohol intoxication and withdrawal at the time of injury, and the effect of a calpain inhibitor (MDL-28170) on cell death following a transection injury. Intoxication had no effect on cell death compared to the TBI condition. In the ethanol withdrawal (EWD) study, EWD did not increase cell death following the TBI except at 72 hours. There was no effect of MDL on cell death. The severity of the model may have caused a ceiling effect. Additionally, imaging points may not have been sufficient for proper characterization. Future studies should use a different injury mechanism and other imaging times should be considered.

Very little is known about the effects of paediatric traumatic brain injury (TBI) on prospective memory, the memory for future intentions such as remembering to post a letter in the morning or do homework. The main aim of this thesis was to redress that shortcoming in the literature. To investigate the effects of paediatric TBI on prospective memory as reliably and fully as possible, the study of children and adolescents with brain injuries was preceded by a developmental study. Given that the process of recovery from brain injury is imposed on the ongoing process of development, it is important to understand more about the normal developmental trajectory of prospective memory first of all. Study 1 compared the prospective-memory performance of 88 normally developing children, adolescents and young adults. The main task was computerised, and its design was influenced by a prefrontal-lobe model because prospective memory is believed to be mediated by the prefrontal regions of the brain. Variables associated with prefrontal-lobe capacity were manipulated: the cognitive demand of an ongoing task, and the importance of the prospective task. Results of Study 1 found that children remembered to respond to fewer prospective cues than adolescents or adults, but that adolescents and adults remembered similarly. Further, the differences between the children's performance and the adolescents' and adults' widened as the cognitive demand of the ongoing task increased. However, the effects of increasing the cognitive demand did not vary between the adolescents and adults. It made no difference to anyone's performance whether the importance of remembering the prospective cues was stressed or not. On the other hand, performance on executive functions, as measured by the Self-Ordered Pointing Task (SOPT), the Stroop Colour Word Interference Test (Stroop), and the Tower of London (TOL), which are also believed to be affected by prefrontal capacity, produced the same age effects as were produced on the computerised prospective-memory task. Further, performance on the SOPT and Stroop predicted performance on the high-demand level of the prospective-memory task. Study 2 compared 34 children and adolescents with TBI with the non-injured children and adolescents from Study 1 on the same tasks. Results revealed that overall those with TBI had poorer prospective-memory performance than their non-injured peers. However, a different pattern of impairment was evident in the children than in the adolescents. Specifically, the children with TBI performed similarly to their non-injured peers, but the adolescents with TBI were significantly worse than the non-injured adolescents. This trend was most noticeable as the cognitive demand of the ongoing task increased. Further, the age and injury effects were reflected in the performances on the executive-function tests, and the TOL predicted performance on the high-demand, prospective-memory task in those with TBI. Study 3 aimed to examine the ecological validity of Study 2, by investigating whether the impairments in prospective memory in young people with TBI measured quantitatively, were matched with qualitative data. Twelve parents of children and adolescents with mild to severe TBI were interviewed about whether or not their children's injuries impacted on their memory (retrospective and prospective) in everyday life. Results showed that in general most children suffered memory losses as a result of their brain injuries, and that prospective-memory loss caused particular hardships for the children and their families. Taken together, the results of the current research revealed that the development of prospective memory reaches a peak of maturity in adolescence, and that adolescents with TBI show greater decrements in prospective memory than adolescents without TBI, but that this pattern is not evident in children, where those with TBI were not significantly different from those without. These findings give support to the prefrontal-lobe model of prospective memory by showing that prefrontal maturity, which reaches a peak during adolescence, reflects the prospective-memory performance of healthy adolescents, and prefrontal injury, which is very common with TBI, shows the effects of deficits more during adolescence than in earlier years when the prefrontal regions are not yet fully developed. Study 3 showed that impairments in prospective memory that result from TBI translate into disabilities in the real world. As a follow up it is recommended that rehabilitation strategies be designed to assist young people with prospective-memory impairments adjust better to school and the demands of everyday living. The prefrontal-lobe model should guide the design of such strategies.

Although it is well established that persons with traumatic brain injury (TBI) experience word retrieval difficulties, the underlying cause of these deficits is not known. Difficulties with word retrieval have negative social implications as they can impact on the ability to converse with others. The overarching goal of this dissertation was to determine the underlying cause of problems with word retrieval after TBI. To test word retrieval in this dissertation, participants were given a series of word fluency tasks and the speed of word generation was measured. In addition to measuring interresponse times, procedures used by Rohrer, Wixted, Salmon and Butters (1995) were also followed. This involved the calculation of parameter estimates to investigate whether slowed retrieval or degraded semantic stores were responsible for the patients� word retrieval difficulties. One parameter (N) was a measure of the total number of retrievable words and the second parameter (tau) was an estimate of mean latency. Study 1 was designed to trial the procedure and equipment adopted throughout this dissertation to analyse speech. University students were presented with categories on a computer screen and asked to generate as many exemplars as possible in 60 seconds. A PowerLab Chart sound system was used to measure the time that each word was generated. The results of Study 1 showed that the methodology of previous research could be replicated using the PowerLab Chart sound system. In Study 2, persons with postconcussion syndrome (PCS) and matched controls were given two word fluency tasks. Results showed that on both tasks patients recalled fewer words, had longer pauses between words, and took significantly longer to generate their first word than controls. Also, patients had a significantly reduced N relative to controls, but there was no difference in tau between patients and controls. Given that the participants had not finished responding and that parameter estimates require responses to be exhausted, Study 3 was designed to replicate the findings of Study 2 using an extended recall period. In Study 3, patients with PCS and matched controls completed a series of word fluency tasks and were given extended periods of time to generate words. Results showed that the patients obtained significantly fewer words on two of the tasks, but no evidence of slowed retrieval was found. There was also no difference in the estimates of N and tau between patients and controls. As the patients in Study 3 sustained more minor injuries than those in Study 2, Study 4 tested patients with severe TBI. In Study 4, patients with severe TBI and matched controls were given a series of word fluency tasks. Results showed that the patients generated fewer words and experienced slowed retrieval. Again, there was no difference in the estimates of N and tau between patients and controls. The results of Study 4 confirmed the hypothesis that slowed word retrieval is a consequence of TBI. Taken together, the results of this dissertation show that an underlying slowness of processing is the primary cause of problems with word retrieval in persons with TBI.

Hyper-activation of N-methyl-D-aspartate receptors (NRs) is associated with excitotoxic cell death during secondary injury following traumatic brain injury (TBI). The efficiency of the NR is dependent on the location of receptors in membrane raft microdomains that provide a platform for coupling of NRs and effector proteins. In many neurodegenerative diseases, activation of the autophagy pathway has been suggested to contribute to glutamate excitotoxicity, but whether increased autophagy signaling contributes to pathology after TBI has not been defined. In these studies, I investigate whether membrane rafts mediate NR signaling and autophagy in cortices of adult male rats subjected to moderate TBI and in sham-operated controls. These studies demonstrate that membrane rafts of the normal rat cortex contain a novel multi-protein signaling complex that links the NR2B glutamate receptor and the autophagic protein Beclin 1. TBI caused a rapid disruption of this complex in which NR2B and pCaMKII were recruited to membrane microdomains. Alteration in NR2B-Beclin 1 association in membrane rafts resulted in activation of autophagy as demonstrated by increased expression of key autophagic proteins Beclin 1, ATG 5 and ATG 7, and significant increases in autophagic vacuoles in neurons of traumatized brains. Administration of the NR2B antagonist RO 25-6981 significantly blocked TBI-induced redistribution of NR2B signaling intermediates and Beclin 1 and delayed the increase in autophagy protein expression in traumatized cortices. Thus, stimulation of autophagy by NR2B signaling may be regulated by redistribution of Beclin 1 in membrane rafts after TBI.