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A mild traumatic brain injury (mTBI), commonly referred to as a concussion, is when the brain experiences an abrupt acceleration and/or deceleration that sends shock waves through the brain tissue, upsetting its structure and function. A mTBI is a heterogeneous condition with acute and chronic outcomes for patients. The chronic form of mTBI can lead to a wide range of neurological, behavioral, and cognitive symptoms. Critically, this injury is not defined by a simple process or pathophysiological event but rather biomechanical and neurological brain damage that can trigger highly complex physiological cascades. These further lead to a wide range of cellular, molecular, and functional changes that alter genes and associated metabolites. These changes, if specifically characterized, could be used to predict a patient’s outcome and recovery timeline. Recently, genetic studies showed that specific genotypes could increase an individual’s risk of more severe injury and impaired recovery following mTBI. Consequently, an improved understanding of gene alteration and genetic changes is necessary to develop personalized diagnostic approaches which can guide the design of novel treatments. The current study proposes utilizing bioinformatic tools, biological networks, and databases to identify potential genes and microRNAs associated with the mTBI in order to aid the early diagnosis of mTBI and track recovery for individual patients. With bioinformatic techniques, we were able to identify and compare genetic and epigenetic data associated with mTBI, as well as understand the various aspects of molecular changes after brain injury. Ultimately, we analyzed and cataloged the biological pathways and networks associated with this injury. A critical search of online bioinformatics databases was performed to determine interactions between mTBI-related genes, and relevant molecular processes. The major finding was that APOE, S100B, GFAP, BDNF, AQP4, COMT, MBP, UCHL1, DRD2, ASIC1, and CACNA1A genes were significantly associated with mTBI outcome. Those genes are primarily involved in different neurological tasks and neurological pathways such as neuron projection regeneration, regulation of neuronal synaptic plasticity, cognition, memory function, neuronal cell death and the dopaminergic pathway. This study predicted specific miRNAs linked to mTBI outcomes and candidate genes (hsa-miR-204-5p, hsa-miR-16-5p, hsa-miR-10a-5p, has-miR-218-5p, has-miR-34a-5p), and RNA-seq analysis on the GSE123336 data revealed that one miRNA found (hsa-miR-10a-5p) matched our predictions related to mTBI outcomes. Pathway analysis revealed that the predicted miRNA targets were mainly engaged in nervous system signaling, neuron projection and cell differentiation. These findings may contribute to developing diagnostic procedures and treatments for mTBI patients who are still experiencing symptoms, but validation of these genetic markers for mTBI assessment requires patient participation and correlation with advanced personalized MRI methods that show concussion related changes. / Thesis / Master of Applied Science (MASc) / Traumatic brain injury (TBI) is a highly prevalent neurological injury affecting millions of individuals globally. Mild TBI (mTBI), sometimes called concussion, makes up over 85% of TBI cases. A mTBI is a heterogeneous condition with acute and chronic outcomes for patients and involves complex cascades of cellular and molecular events that can lead to functional changes in genes and associated metabolites. In recent genetic studies, it has been shown that certain genotypes are associated with a higher risk of experiencing a more serious injury and a slower recovery after mTBI. These genes can be utilized as crucial biomarkers to predict how long it will take for a person to recover from a concussion. The purpose of this study was to find potential biomarkers that could help in the early detection of mTBI and the monitoring of individual patients’ recovery. It was hypothesized that genes and miRNAs (and their associated proteins) involved in neuronal body, axonal and myelin integrity and regeneration would be identified as important markers of severity.

Objective: Identify patients with specific emergency department (ED) discharge diagnoses who later report symptoms associated with a mild traumatic brain injury (MTBI), compare frequency and severity of MTBI symptoms by discharge diagnoses, investigate the frequency of head injury education provided to ED patients with each diagnosis, and finally, to learn what type of changes have occurred in the lives of patients as a result of their injury. Methods: Fifty-two ED patients, aged 18 to 28 who were at least two weeks post injury, spoke English and were discharged with a diagnosis of concussion/closed head injury (CHI), head laceration, motor vehicle crash (MVC), whiplash/cervical strain, facial/jaw fractures or multiple injuries were invited to participate. Participants completed the Post Concussive Symptom Scale (PCSS), a demographic questionnaire and then a series of open-ended questions about the impact the injury had on their lives. Results: MTBI symptoms on the PCSS were reported by 84.6% (n = 44) of respondents with a range of 1 – 23 different symptoms per participant. Headache (69.2%) and fatigue (61.5%) were the most common symptoms. Males (51% of the participants) reported on average 6.76 symptoms (S.D. = 6.53) whereas females reported an average of 12.68 symptoms (S.D. = 6.32). A large percentage (83.3%, n = 10) of participants with a MVC diagnosis reported severity scores in the moderate range (mean = 3.17; S. D. = 0.27) in all four PCSS categories (physical, thinking, sleep and emotional) representing the highest severity scores reported overall. Participants diagnosed with a concussion/CHI received the most (74%) head injury education of all discharge diagnoses, but only half (51%) received written information. The most common quality of life change was that 70.3% of survey participants became more cautious. Conclusion: Participants with a discharge diagnosis not commonly associated with brain injury reported having MTBI symptoms at least two weeks post injury with females reporting twice as many symptoms as males reported. Head injury education provided in the ED was lacking for all participants and although participants involved in a MVC reported having the most severe MTBI symptoms they had the least head injury education. All health care providers, especially nurses working in the ED, need to look beyond physical complaints and recognize injuries associated with increased risk for developing MTBI symptoms. Proactive ED identification of patients with "at risk" injuries by nurses would likely promote increased MTBI education and thereby result in fewer missed MTBI diagnoses.

Thesis (Ph.D.)--Boston University / The widespread use of Improvised Explosive Devices (IEDs) in the Wars in Iraq and Afghanistan has caused a dramatic increase in shockwave-induced mild Traumatic Brain Injury (mTBI), leading mTBI to be dubbed the 'signature injury' of modern warfare. Currently, the pathology of shockwave-induced mTBI is unknown , and it is diagnosis is based on self-reported symptoms and combat history. While the etiological mechanism has not yet been determined , it is becoming increasingly accepted that shockwaves themselves are the brain-damaging agent that emanate from IEDs. To assess how mild, sub-lethal shockwaves might damage brain tissue, we developed an in vitro assay to deliver shockwaves to neuronal cells in culture, and then assayed several properties of these cells that affect their function. This assay involved exposing rat cortical and hippocampal primary neuronal cultures to shockwaves of increasing magnitude generated with a biolistic Gene Gun. The Gene Gun produces shockwaves of sufficient overpressure to cause cognitive impairment in animal models of shockwave-induced mTBI. Our results show that overpressures of ~1.0 pound per square inch (psi) caused transient membrane permeability for molecules up to ~12 nanometers in diameter. This change in membrane permeability was accompanied by a transient decrease in cellular ATP levels and synaptic densities. This synaptic degeneration correlated with changes in the level and phosphorylation state of several synaptic proteins examined. Similar results were observed in dissected rat retinas suggesting that these shockwave-induced effects can occur in complex tissues, such as the brain. Based on these findings we propose that shockwaves damage cellular membranes, leading to a decrease in intracellular ATP, and ultimately to a reduced numbers of synapses, the part of neurons most important for learning, memory and behavior. Additional experiments in whole animals will be required to ascertain whether shockwave-induced cellular damage and synaptic degeneration plays an etiological role in shockwave-induced mTBI.

Within the past few decades brain injury, or traumatic brain injury (TBI), has gained widespread attention. Early focus was on more severe forms of TBI; severity typically measured using the Glasgow Coma Scale. In more recent years, however, mild traumatic brain injury (mTBI), most notably concussions, has gained increasing interest due to the high frequency of concussions suffered in athletes of all levels and, recently, in military personnel due to blast injuries. Studies being performed have focused not only on ways to help minimize the incidence of concussion as well as treating concussive symptoms, but also on detecting concussions. Many concussions go unreported due to inadequate knowledge of concussive symptoms amongst the general population. Because many concussions go unnoticed and hence unreported the individual who has sustained a concussion is at risk for a more serious injury in the future. One such injury is Second Impact Syndrome (SIS). Second Impact Syndrome is essentially a synergistic event where the sum of two seemingly mild concussions combine to create an event that is potentially fatal. The findings during the autopsy are that there is insignificant damage to the brain to cause death. The damage that occurs, however, is on a molecular level causing a strain on the metabolic processes of the brain called dysautoregulation. Without an understanding of the changes that have occurred on a molecular level in SIS the assignment of cause and manner of death is difficult for the medical examiner. Currently, in order to diagnose SIS, a thorough scene investigation, along with the documentation of a previous head injury is needed. Without a full understanding of SIS and the pathophysiology changes that take place a medical examiner (ME) could misclassify the cause and manner of death in a death due to SIS. In the future, eliminating the prerequisite of identification and documentation of previous head injuries in order to diagnose SIS is needed. This paper evaluates the literature on the current knowledge of TBI and concussions in an attempt to create a protocol on how a medical examiner should approach a case where autopsy findings are unremarkable.

With chronic post surgical pain affecting up to one third of patients undergoing surgeries and the price of treatment being astoundingly high there has been a transition in research to investigate and identify risk factors. Through identification of risk factors new preventative measures can be taken to ensure better surgical outcomes. The role that psychosocial factors can play in the development of chronic post surgical pain has long been recognized yet its mechanisms are still unknown. We aim to investigate how environment can play a direct role in pain perception and sensitivity. We used a Chronic Mild Stress (CMS) paradigm to induce depression in 10 adult male mice, we used 10 control mice who were left in standard opti cages, and 10 enriched mice who were placed in large enrichment cages. CMS mice were exposed to a series of stressors and all mice underwent spared nerve injury surgery. During spared nerve injury the common peroneal and tibial branches of the sciatic nerve were severed while the sural branch was left intact. Overall well-being and pain threshold of mice were tested via Von Frey, Hot Plate, Heat Place Preference, Dynamic Weight Bearing, Hole Board, and Social Interaction. It was found that CMS mice experienced thermal hyperalgesia yet normal thermal threshold sensation. CMS mice also spent less time interacting with novel mice in social interaction, and less amount of time exploring the center of the hole board arena than control or enriched mice. While Von Frey results did not change over the course of the experiment, dynamic weight bearing results indicated spared nerve injury surgery was successful and produced chronic pain. Results indicate that environment plays a role in thermal pain perception and CMS affected overall well being of mice as CMS mice exhibited more timid and anxious behavior.

Alzheimer's disease (AD) is neurodegenerative disorder that causes memory loss and cognitive dysfunction. It affects one in five people over the age of 80 and is distressing for both sufferers and their families. A transitional stage between normal ageing and dementia including AD is termed a mild cognitive impairment (MCI). Recent studies have shown that people with MCI may convert to AD over time although not all MCI cases progress to AD. Much research is now focussing on early detection of AD and diagnosing an MCI that will progress to AD to allow prompt treatment and disease management before the neurons degenerate to a stage beyond repair. Hence, the ability to obtain a method of identifying MCI is of great importance. Virtual reality plays an important role in healthcare and offers opportunities for detection of MCI. There are various studies that have focused on detection of early AD using virtual environments, although results remain limited. One significant drawback of these studies has been their limited capacity to incorporate levels of difficulty to challenge users' capability. Furthermore, at best, these studies have only been able to discriminate between early AD and healthy elderly with about 80% of overall accuracy. As a result, a novel virtual simulation called Virtual Reality for Early Detection of Alzheimer's Disease (VREAD) was developed. VREAD is a quick, easy and friendly tool that aims to investigate cognitive functioning in a group of healthy elderly participants and those with MCI. It focuses on the task of following a route, since Topographical Disorientation (TD) is common in AD. An investigation was set up with two cohorts: non-elderly and elderly participants. The findings with regard to the non-elderly are important as they represent a first step towards implementation with elderly people. The results with elderly participants indicate that this simulation based assessment could provide a method for the detection of MCI since significant correlations between the virtual simulation and existing neuropsychological tests were found. In addition, the results proved that VREAD is comparable with well-known neuropsychological tests, such as Cambridge Neuropsychological Automated Test Battery, Paired Associate Learning (CANTAB PAL) and Graded Naming Test (GNT). Furthermore, analysis through the use of machine learning techniques with regard to the prediction of MCI also obtained encouraging results. This novel simulation was able to predict with about 90% overall accuracy using weighting function proposed to discriminate between MCI and healthy elderly. / Ministry of Higher Education, Malaysia and University Sultan Zainal Abidin, Malaysia (UNisZa)

Children and youth who suffer a mild traumatic brain injury or concussion are at risk for a number of negative outcomes. The symptoms of concussion and the management of these symptoms can be disruptive to the child’s everyday activities, especially if they are prolonged. Depression can result and may complicate the course of recovery. Depression has overlapping symptoms with concussion and is thought to lengthen the recovery period. There has been much research done in populations of mixed severities of brain injury but very little addresses children with concussion. Knowledge in this area is crucial due to depression’s impact on all aspects of functioning as well as the potential alteration of the child’s developmental trajectory. The purpose of this research was to examine the risks and predictors of depression following concussion in youth and to explore the experiences of a subsample of youth and their families with prolonged recovery from concussion, complicated by depression. Chapter One provides a review of the current literature setting the context for the research within what is known about concussion in youth, what is known about depression in youth and because of the early stages of this type of research, what is known about depression as an outcome of concussion in all age groups. Chapter Two presents a study highlighting the tangible risk for depression in a sample of children being followed in a tertiary care clinic (N=92). Significant predictors of depressive symptomatology were found to be the need for hospital admission and high symptom scores in the first few days and weeks after injury, which may be valuable information for prevention, early identification and treatment of youth at risk for depression after concussion. Chapter Three provides an in-depth exploration of the experiences of youth and families who have gone through prolonged recovery from concussion with significant depressive symptomatology. A phenomenological approach was used with six participants and their families who were interviewed and their responses analyzed. A trajectory of recovery was identified; common themes within each of four key stages of the trajectory were discussed and illustrated using direct quotes from the participants. Chapter Four outlines the important implications of these two studies for health care professionals; particularly in raising awareness of the mental health outcomes of concussion. Knowledge of the impact of debilitating symptoms, activity restrictions and depression can inform discussions early after a concussion to prepare and possibly prevent some of the losses experienced by youth that can lead to depression. / Thesis / Master of Science Rehabilitation Science (MSc)

<p> Dynamic stress tests were performed on mild steel samples. The material parameters 'n' and 'G(εᵣ, tₒ)', defined as 'stress dislocation velocity exponent' and 'flow function' respectively, were evaluated using the equation "σₘⁿtₒ K(n) = G(εᵣ, tₒ)" as proposed by Kardos (1). The values determined for 'n' are in agreement with the results obtained by other researchers using different techniques. </p> <p> The equipment for studying the response of materials to dynamic loading was modified to permit a wider duration range for the loading. </p> <p> A technique was developed to monitor the pressure of the oil in the intensifier throughout the entire loading cycle. </p> / Thesis / Master of Engineering (ME)

Each year in the United States, approximately 1.35 million people are a ected by mTBI (aka concussion) and subsequent cognitive impairment. Approximately 33% of mTBI cases results in persistent long-term cognitive de cits despite no abnormalities appearing on conventional neuroimaging scans. Therefore, an accurate and reliable imaging method is needed to determine injury location and extent of healing. The goal of this study was to characterize and quantify mTBI through DTI, an advanced MRI technique that encodes voxel-wise tissue water microstructural di usivity as a tensor, as well as QSM, which measures iron deposition within tissues. We hypothesized that personalizing the analysis of DTI and QSM will provide a better understanding of trauma-induced microstructural damage leading to improved diagnosis and prognosis accuracy. Through regression analysis, a preliminary comparison between DTI data to QSM measurements was performed to determine potential correlations between the two MRI techniques. Further, a large database of healthy pediatric brain DTI data was downloaded and each was warped into a standardized brain template to ultimately use for voxel-wise z-score analysis of individual mTBI patients (n=26). This allowed localization and quantitation of abnormal regions on a per-patient basis. Signi cant abnormalities were commonly observed in a number of regions including the longitudinal fasciculus, fronto-occipital fasciculus, and corticospinal tract, while unique abnormalities were localized in a host of other areas (due to the individuality of each childs injury). Further, through group-based Bonferroni corrected T-test analysis, the mTBI group was signi cantly di erent from controls in approximately 65% of regions analyzed. These results show that DTI is sensitive to the detection of microstructural changes caused by mTBI and has potential to be a useful tool for improving mTBI diagnosis accuracy / Thesis / Master of Applied Science (MASc) / Concussions affect over one million people in the United States each year. In a number of cases, these individuals must cope with persistent long-term cognitive impairment resulting from the injury. A current, significant problem is that concussion cannot be reliably diagnosed using conventional CT and MR imaging methods. Therefore, an accurate and reliable imaging method is needed to determine both injury location and severity, as well as to monitor healing. The goal of this study was to quantify concussion through MR imaging techniques known as Di ffusion Tensor Imaging and Quantitative Susceptibility Mapping, which accurately model the brain's mi- crostructure. Analysis utilizing these MRI methods found signifi cant abnormalities in a number of brain regions of concussed subjects relative to healthy individuals. These results suggest that DTI, in particular, is sensitive to microstructural changes caused by concussions and has the potential to be a useful tool for improving diagnosis accuracy.