A quiet stance framework and a control system perspective were used to explore healthy balance and balance after mild traumatic brain injury. Linear and non-linear centre of pressure analyses were applied. The foundation was laid by reviewing literature to understand how balance is achieved, how it is represented as a control system, what factors are known to affect balance, and the cornerstone—how to choose appropriate measures to quantify balance. To understand how mild traumatic brain injury affects the brain, a scoping review of the evolution of symptoms and effects was used to form a conceptual description. Findings described phases of functional effects that resulted from neurometabolic cascade; consequently, balance and dual-task functional effects were determined to stem from widespread not focal changes in the brain. Subsequent studies were tailored to address gaps in knowledge. Linear and non-linear centre of pressure measures were first investigated in healthy young adults to determine what supplemental information could be provided by non-linear measures describing local stability and scaling. It was found that linear and non-linear measures were complementary in assessing balance system input-output, control, and integration. Furthermore, normative non-linear data were established for single leg and tandem stance. Subsequently, these measures were investigated in young adults and adolescents with recent mild traumatic brain injury based on the hypothesis that altered mechanisms affecting balance would be reflected by changes in these measures. In young adults, increased complexity of short-term scaling indicated subtle changes to balance control after injury. In adolescents, linear and non-linear measures also demonstrated changes to output, control, and temporal relations of balance. Altered balance was also demonstrated while concurrently performing a Stroop task. On the whole, changes to multiple aspects of balance supported the concept of widespread effects resulting from mild traumatic brain injury. Balance control in quiet stance was further explored using three-dimensional state space reconstruction of centre of pressure. Visual representations demonstrated that dynamic structure within centre of pressure reflected control characteristics. These control characteristics were still present after mild traumatic brain injury.

Traumatic Brain Injury (TBI) is a growing global health problem. Mild forms of TBI (mTBI) such as concussions, represent the most common manifestation of this type of injury with children and youth (< 20 years old) among the most likely to sustain mTBI. There is growing evidence for the cumulative effects of repeated mTBI (rmTBI) suggesting that while a single concussion may not cause evident or long-lasting brain alterations, the summation of multiple mTBI may lead to more severe consequences. In contrast to severe TBI, lesions in mTBI patients are challenging to detect. Despite this, mTBI patients may still present with cognitive and emotional deficits. Cerebral microbleeds (CMBS), a subtle form of vascular damage, have been identified as an early hallmark in brain trauma and several neurodegenerative diseases. The cumulative effects of subtle but sustained microvascular damage could explain the persistent long-term functional deficits observed in mTBI. In this study, the awake closed-head injury (ACHI) model was used to investigate the association between rmTBI and microvascular damage in different brain regions in both male and female juvenile rats at one and seven days after the last injury. The results indicate that the injury paradigm used in this study (i.e. 8 impacts over 4 days) using the ACHI model is associated with an acute increase in sings of microvascular damage in both sexes that is no longer evident at a longer time point. These study is the first to describe the negative impact of rmTBI on CMBs in the juvenile using an awake animal model, and provides evidence for the potential involvement of this subtle form of vascular damage in the development of neurological deficits after rmTBI. / Graduate

Despite being a common problem, there are many gaps in the understanding of mild traumatic brain injury (mTBI). Its pathophysiology is unclear, diagnostic criteria are variable, and the associated symptomatology is non-specific. As a result, there are challenges associated with precise mTBI diagnosis and treatment. The dissertation seeks to identify distinctive features, both clinical and pathophysiological, exclusively associated with mTBI. In addition, the neuroinflammatory component of mTBI is explored in detail in the context of inflammatory cytokines’ potential use as prognostic biomarkers and development of a targeted treatment. Three studies were conducted to explore mTBI. We conducted a retrospective chart review to identify the clinical presentation exclusively associated with mTBI that sets it apart from other similar conditions. This was accomplished through symptomatology comparison between the patients with head injuries that meet the ACRM (1993) criteria for mTBI diagnosis vs. those who do not. The results of this study showed that 20.5% of patients with chronic post-concussive symptoms do not meet the ACRM (1993) criteria of mTBI despite sustaining a head injury. In addition, no symptom specific differences were found between the two populations. A detailed systematic review and meta-analysis were also conducted to identify the common inflammatory cytokines associated with mTBI and to explore their potential use as prognostic biomarkers. The results show significantly elevated blood IL-6, IL-1RA, IFN-γ (at <24 hrs.) and MCP-1/CCL2 (within a week) levels in patients with mTBI compared to healthy controls in majority of the included studies. A meta-analysis was further conducted that supported these findings by showing significantly elevated IL-6, MCP-1/CCL2, and IL-1β levels in patients with mTBI in the acute stages (<7 days). In addition, elevated IL-6, TNF-α, IL-1RA, IL-10, and MCP-1/CCL2 levels were associated with poor prognosis in patients with mTBI. In addition, a systematic review was conducted to identify the inflammatory cytokines associated with adverse psychological outcome in population with mTBI. The results show that IL-6, TNF-α, IL-10, and CRP are associated with PTSD and/or depression in the population with mTBI, particularly in the chronic stages. Collectively, these studies show that all symptomatic patients with head trauma, whether or not they meet the subjective criteria of mTBI, should be managed and offered early rehabilitation to avoid long tern adverse consequences. In addition, this thesis supports the neuro-inflammatory hypothesis of mTBI and identifies inflammatory cytokines that could be potentially utilized as prognostic biomarkers and for the development of mTBI treatment. / Thesis / Doctor of Philosophy (PhD)

With the desired deployment of Artificial Intelligence (AI), concerns over whether AI can “communicate” why it has made its decisions is of particular importance. In this thesis, we utilize predictive entropy (PE) as an surrogate for predictive uncertainty and report it for various test-time conditions that alter the testing distribution. This is done to evaluate the potential for PE to indicate when users should trust or dis- trust model predictions under dataset shift or out-of-distribution (OOD) conditions, two scenarios that are prevalent in real-world settings. Specifically, we trained an ensemble of three 2D-UNet architectures to segment synthetically damaged regions in fractional anisotropy scalar maps, a widely used diffusion metric to indicate mi- crostructural white-matter damage. Baseline ensemble statistics report that the true positive rate, false negative rate, false positive rate, true negative rate, Dice score, and precision are 0.91, 0.091, 0.23, 0.77, 0.85, and 0.80, respectively. Test-time PE was reported before and after the ensemble was exposed to increasing geometric distortions (OOD), adversarial examples (OOD), and decreasing signal-to-noise ratios (dataset shift). We observed that even though PE shows a strong negative correlation with model performance for increasing adversarial severity (ρAE = −1), this correlation is not seen under distortion or SNR conditions (ρD = −0.26, ρSNR = −0.30). However, the PE variability (PE-Std) between individual model predictions was shown to be a better indicator of uncertainty as strong negative correlations between model performance and PE-Std were seen during geometric distortions and adversarial ex- amples (ρD = −0.83, ρAE = −1). Unfortunately, PE fails to report large absolute uncertainties during these conditions, thus restricting the analysis to correlative relationships. Finally, determining an uncertainty threshold between “certain” and “uncertain” model predictions was seen to be heavily dependant on model calibra- tion. For augmentation conditions close to the training distribution, a single threshold could be hypothesized. However, caution must be taken if such a technique is clinically applied, as model miscalibration could nullify such a threshold for samples far from the distribution. To ensure that PE or PE-Std could be used more broadly for uncertainty estimation, further work must be completed. / Thesis / Master of Applied Science (MASc)

In the past decade, numerous studies have examined the correlation between repetitive head trauma in athletes who participated in contact sports and the development of various personality, behavioral, and cognitive changes. Autopsy data from these athletes have uncovered unique patterns of neuropathology that are believed to be associated with the observed clinical symptoms, and together characterize a condition known as chronic traumatic encephalopathy (CTE). Historically, the condition was known as “dementia pugilistica” commonly found in boxers; however, recent studies have identified cases of CTE in retired football players, hockey players, soccer players, war veterans, and other non-athletes. CTE is a progressive disease and clinical signs often appear many years after the trauma. These symptoms frequently include depression, aggression, suicidality, short-term memory loss, and executive functioning impairments. Postmortem examinations of individuals with CTE reveal distinct gross and microscopic pathology, including atrophy of the frontal and temporal cortices, sulcal accumulation of hyperphosphorylated tau, -amyloid deposition, and TAR DNA-binding protein 43 abnormalities. Although current hypotheses suggest that repetitive head trauma causes the development of CTE, the lack of prospective studies hinders our ability to definitively determine its etiology. Likewise, the inability to diagnose CTE in vivo has constrained our attempts to systematically examine the disease’s progressive nature. The goal of this paper is to review the past and current literature on CTE in boxers and football players. We also discuss current hypotheses concerning CTE’s clinical presentation and neuropathology, and situate CTE within the context of other neurodegenerative diseases. Finally, we address the current limitations of CTE research and propose key objectives for future studies.

Traumatic Brain Injury (TBI) is a global health problem and concussion, or mild TBI (mTBI), accounts for up to 75% of all brain injuries occurring annually in the US. There is also growing awareness that repeated mild traumatic brain injury (r-mTBI) can result in cumulative neuropathology and learning and memory deficits, however there is a paucity of preclinical data as to the extent these deficits manifest. R-mTBI in juvenile populations is of special interest as not only is this a high risk group, but this is also a time period when the human brain continues to mature. The hippocampus is a brain region important for learning and memory processes, and r-mTBI during the juvenile period may particularly disrupt the development of cognitive processes. To examine this issue we used a model of awake closed head injury (ACHI), and administered 8 impacts over a 4 day period to juvenile male and female rats (P25-28). At 1 or 7 days after the last injury, a cohort of rats was used for behavioural testing to study anxiety and risk-taking behaviours and cognitive abilities. From a different cohort, hippocampal slices were generated and used for in vitro electrophysiological recordings, and the capacity for long-term depression (LTD) and long-term potentiation (LTP) was examined in the medial perforant path (MPP)-dentate gyrus (DG) synapse. Our results showed that r-mTBI impaired hippocampal-dependent spatial learning and memory and that r-mTBI significantly impaired the capacity for LTD but not LTP in both sexes. These data are the first to describe the negative impact of r-mTBI on LTD in the juvenile DG in both males and females, and provide evidence for the delayed development of neurological deficits with r-mTBI. / Graduate

Post-concussion syndrome (PCS) is a poorly understood sequela of mild traumatic brain injury (mTBI), more commonly referred to as concussion. While PCS is known to affect a subset of individuals following injury, it remains unclear how and why specific individuals incur chronic symptoms. Concussions disrupt normal neurophysiologic function within the brain, however the neurophysiologic underpinnings of PCS are unclear. Using transcranial magnetic stimulation (TMS), it is possible to non-invasively investigate neurotransmission in clinical populations such as those with PCS by stimulating the primary motor cortex (M1) and recording motor outputs in a contralateral hand muscle. A study was conducted using TMS to measure corticospinal excitability, intracortical facilitation and inhibition, and transcallosal inhibition in M1 of a group with PCS and a non-injured, healthy control group. Greater corticospinal excitability, and specific reductions in intracortical and transcallosal inhibition were observed in the PCS group, providing evidence of impaired neurotransmitter receptor activity. Importantly, these findings differed from previous observations in recovered concussion groups using similar stimulation techniques. Furthermore, it was observed that these neurophysiological differences may relate specifically to the presence of depression symptoms rather than general concussion symptoms. The physiologic and clinical implications of the findings of this thesis are discussed, and novel research avenues warranting investigation are identified. / Thesis / Master of Science in Kinesiology

The purpose of this study was to examine the effects of aerobic fitness level on concussion risk, severity and recovery in high school football players. Participants (N=158) completed aerobic fitness (i.e., estimated VO2 max) and baseline neurocognitive tests (i.e., ImPACT). Concussed athletes completed ImPACT every 24-72 hours until they were asymptomatic or returned to baseline levels. A post-season questionnaire assessed unreported concussions and symptoms. Twenty players incurred concussions. Previously concussed athletes were 3.71 times more likely to be concussed than those with no concussion history. Severely concussed participants reported lingering symptoms. Previously concussed athletes high in aerobic fitness reported fewer symptoms than those low in aerobic fitness. Non-significant trends suggested that aerobic fitness might be related to faster recovery times and fewer symptoms. Twenty-eight percent (n= 38) of non-concussed participants reported a potential concussion and symptoms that were not recorded by medical staff during the season.

Primary objective. The goals of this project were to review the current literature regarding the role of the speech-language pathologist (SLP) in concussion management and to conduct a survey of SLPs with experience in concussion care to determine their current practices and perspectives. Design and methods. An online survey consisting of 41 questions was emailed to SLPs throughout the U.S. and Canada. Responses were anonymously collected from 60 SLPs, and the responses were analyzed. Results and conclusions. Results showed that SLPs who work in concussion care are generally knowledgeable and confident despite how recently concussion has become part of SLP practice. There has been improvement in the types of assessment tools used in concussion cases, but there is a need for more sensitive instruments. Findings point to the need for increased availability of concussion training for SLPs and the need for continued research into current clinical practices.

The incidence of concussive injury has continued to arise annually with up to 3.8 million concussions reported per year (Thurman 1999) and 15% of these injuries occurring with persistent symptoms (Kraus and Chu, 2005). Few studies have examined the differences between youth and adult concussion (Yeates et al, 2012; Gosselin et al, 2010) therefore it is unknown whether youth and adults pose a similar risk of sustaining a concussion following impact. For this reason, the purpose of this study is to determine if differences exist in the dynamic response of the head and brain tissue deformation characteristics between children and adolescents for falls in comparison to adult data which have resulted in concussive injuries. Patient data was collected from emergency room hospitals across Canada. After exclusion criterion was applied, 11 child and 10 adolescent falls were reconstructed using mathematical (MADYMO) model, physical model (Hybrid III Headforms) and finite element modelling. Both groups were compared to each other as well as an adult group collected by Post et al (2014b) using a one-way ANOVA and Welsh test. The results of this study show that the children produced the lowest values for all variables when compared to the adolescents and adults whereas the adolescents produced the largest (with the exception of MPS where the adolescent and adult MPS was the same). Although all results were above the suggested thresholds for risk of concussive injury, the youth produced the lowest brain tissue strain yet still suffered a concussion. This is important to note as it may suggest that children are at an increased risk of injury at a lower brain tissue strain level. Understanding the differences in parameters influencing concussive injury may aid researchers in comprehending the unique risk for youth at difference ages. This information would be useful in terms of protective equipment design, promoting safe play in games and management of patients following injury.