Concussions are the injury and symptoms that can result from transmission of a biomechanical force to the brain. They represent a significant global health burden, and are the subject of a growing body of medical research. A concussion can only be definitively diagnosed by a medical professional based on symptoms, although advanced neuroimaging and biomarker-based approaches are promising future diagnostic tools. There is no treatment for concussion beyond following return-to-work or -play guidelines, which recommend avoiding strenuous physical and cognitive activities until they no longer exacerbate symptoms. Preclinical models of concussion have been used to examine pathophysiological processes underlying symptoms, which is an important step in developing tools for diagnosis and treatment. Historically the clinical translation of preclinical concussion research has been limited, and the use of anaesthesia, and preference for adult male rats may contribute to this. These means of reducing variability are justified, but preclinical research moving forward should address these limitations to translatability by including more clinically relevant subjects and avoiding anaesthesia. To this end, we developed a new preclinical model for pediatric concussion. Our awake closed head injury (ACHI) model is well-suited to this purpose because it produces a helmeted closed-head injury involving vertical and rotational displacement of the head, and does not require anaesthesia. Before the ACHI model can be used to investigate concussion mechanism, diagnosis, and treatment, it needs to be characterized to demonstrate that it produces clinically relevant neurobehavioral and pathological changes. We developed a modified neurologic assessment protocol to test neurologic function immediately after each injury. The Barnes maze, elevated plus maze, open field, and Rotarod were used to measure injury-related changes in cognition, anxiety, and motor function. The Barnes maze reversal task was used to detect more subtle cognitive impairments of executive function. Structural MRI was used to search for visible lesion, hemorrhage, or atrophy; and silver-stain histology was used to detect neurodegeneration. We determined repeated ACHI produced acute neurologic impairment with the NAP, and a mild spatial learning deficit potentially mediated impaired cognitive flexibility in the Barnes maze and reversal training. These were accompanied by neurodegeneration in the optic tract, hippocampus, and ipsilateral cortex during the first week of recovery. Thus, following the internationally recognised definition developed by the concussion in sport group, we demonstrated 1) an “impulsive” force transmitted to the head results in 2) the rapid onset of short-lived neurologic impairment that resolves spontaneously. This occurs 3) with normal structural neuroimaging, and 4) produces cognitive impairment, and LOC in a subset of cases. The ACHI model is the first in Canada to forego anaesthesia, and this is the first demonstration of neurocognitive impairment accompanied by diffuse neurodegeneration in the absence of structural MRI abnormalities after mild traumatic brain injury in juvenile male and female rats. / Graduate

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.

Children and adolescents with concussion display aberrant functional connectivity in some of the major neurocognitive networks. This includes the Default Mode Network, Central Executive Network and Salience Network. Using resting state fMRI, the purpose of this thesis was to explore the functional connectivity of cognition-related networks in youth experiencing concussion. With a prospective cohort study, the functional connectivity (defined as the temporal coherence between spatially separated brain regions) of children and adolescents ages 10-18 years old was evaluated in relation to a number of demographic and injury-specific factors including recovery length, age at the time of injury, symptom severity, and neurocognitive performance. The results showed two general trends: (1) a reduction in connectivity (i.e., hypoconnectivity) between the regions of the Default Mode Network, and (2) an increase in connectivity (i.e., hyperconnectivity) between additional sensory-related regions like the cerebellum and hippocampus. The Default Mode Network, which processes self-referential information, has a long-protracted development across childhood through adulthood. Given that the participants in this cohort exhibited reduced functional connectivity within the Default Mode Network and between the Default Mode Network and other neurocognitive networks suggests that this is an area of vulnerability in youth in the event of concussion. Increased connectivity between the Central Executive Network and Salience Network, and between cognitive- and sensory-related regions such as the hippocampus and cerebellum might be interpreted as a compensatory mechanism to supplement deficits of the Default Mode Network. This thesis sheds light on important concussion-related regions for future research to investigate further and delves into the possible neural mechanisms contributing to the cognitive, sensory, mood, and sleep disturbances in children and adolescents with concussion. / Dissertation / Doctor of Philosophy (PhD) / Your brain at rest is not resting. In fact, your many brain regions are continuously communicating even during rest to maintain important communication between them. This communication between brain regions is termed functional connectivity. When you receive a blow to the head, face, neck, or another part of your body that senses a biomechanical force to your brain, the functional connectivity (i.e., communication lines) between your brain regions may be altered. A blow of this nature is considered a concussion, also known as a mild traumatic brain injury. With disruptions to the typical functional connectivity between your brain regions following a concussion, you may experience difficulty in managing cognitive tasks, emotions, and body coordination. Among those most vulnerable to the effects of concussion are children and adolescents whose brains have yet to develop fully. The goal of this thesis was to evaluate the functional connectivity between brain regions of children and adolescents to determine how brain communication might be disrupted following concussion. These evaluations were done using functional magnetic resonance imaging (fMRI) of the brains of children and adolescents ages 10-18 years old. It was discovered that the functional connectivity of the frontal lobe is related severity of post-concussion symptoms such that individuals with worse symptoms had reduced functional connectivity in the frontal lobe compared to individuals who reported less severe symptoms. Further, children and adolescents with longer recovery periods have a different level of functional connectivity in the temporal lobe compared to youth with relatively shorter recovery periods. This might suggest that both of these regions could provide prognostic value in determining who might have worse symptoms or a longer recovery time following injury. In comparison to children and adolescents who have not had a concussion, children and adolescents experiencing a concussion are more likely to have abnormal functional connectivity between the hippocampus and cerebellum, which are particularly involved in processing sensory information and navigation. This was interpreted to mean that the brain responded to the concussion by increasing the communication between regions that might help a child with a concussion coordinate their bodies so that they can move from place to place. This was additionally supported by a further investigation which showed that children and adolescents have reduced communication between areas of the brain that might allow them to process information about the self (e.g., memories, sensations, relationships with others, etc.). Overall, the results demonstrated that following a concussion, children and adolescents may have a deficit in the functioning of the frontal lobe in a specific region that allows them to process cognitive and sensory information. This might explain why concussion leads to poor memory, body coordination, sensitivity to light and sounds, and even difficulty sleeping. Their brains might then compensate for the disruption by increasing alternate pathways of communication. Together these findings open gateways for future researchers to look more deeply at the specific regions affected by concussion in youth. It draws attention to the many neurocognitive, emotional, and somatic symptoms a child with a concussion exhibits and their symptoms’ underlying neurological processes.

Subconcussive impacts have become a growing concern particularly with respect to contact sports. It is believed that minimal head impacts can cause cerebral perturbations that initiate an immune response creating a window of vulnerability. Evidence suggests that additional head insults sustained during this window of vulnerability elicit an exaggerated inflammatory response and exacerbate cognitive deficits. Therefore, determining the lower limits of systematic perturbation resulting from low-level impacts is of critical importance in expanding our understanding of cerebral vulnerability and recovery. However, the vast majority of experimental investigations of subconcussion fail to model single impact events and instead focus on cumulative insults. Additionally, these animal models employ impact magnitudes used to model mild Traumatic Brain Injury. The present investigation aimed to address this gap in knowledge through the utilization of a pneumatically controlled, closed-head, blunt impact device capable of producing repeatable, defined, subconcussive head impacts within a rat model. Thermography was used as a noninvasive measure of inflammation and system perturbations with respect to local (head) and global (thorax and abdomen) temperature changes. Cognitive function was assessed using an Open Field Test and Novel Object Recognition test. Neuroinflammation was measured by assessment of GFAP and iba-1 within the hippocampus and corpus callosum. To investigate the tolerance and the persistence of cerebral vulnerability, measurement outcomes were assessed at six timepoints of recovery, 0, 0.5, 1, 4, 7, and 14 days. Thermal disturbances were detected directly after impact, followed by an apparent recovery, 0.5- and 1-day post-impact. A latent temperature increase was observed after 4- and 7-days of recovery coinciding with decreased risk-avoidance behaviors, a modest upregulation of iba-1, and a marked downregulation of GFAP. Short-term memory deficits became apparent after 7-days of recovery. A decrease in locomotor activity and an upregulation of GFAP was observed concomitant to a persistent decrease in risk-avoidance despite thermal, short-term memory, and iba-1 measurements recovery 14-days post-impact. Overall, these results indicate that low magnitude subconcussive impacts can produce latent thermal, behavioral, and histological disturbances uncharacteristic for a head injury model suggestive of a biomechanical threshold of altered pathodynamics that fail to fully recover after 14 days.

Assessment of diffuse brain disorders, where the brain may appear normal, has proven difficult to translate into personalized treatments. Previous methods based on brain magnetic resonance imaging (MRI) resting state blood oxygen level dependent (rs-BOLD) signal routinely rely on group analysis where large data sets are assessed using region-of interest (ROI) or probabilistic independent component analysis (PICA) to identify temporal synchrony or desynchrony among regions of the brain. Brain connectivity occurs in a complex, multilevel and multi-temporal manner, driving the fluctuations observed in local oxygen demand. These fluctuations have previously been characterized as fractal, as they auto-correlate at different time scales. In this study we propose a model-free complexity analysis based on the fractal dimension of the rs-BOLD signal, acquired with MRI. The fractal dimension can be interpreted as a measure of signal complexity and connectivity. Previous studies have suggested that reduction in signal complexity can be associated with disease. Therefore, we hypothesized that a detectable differences in rs-BOLD signal complexity could be observed between patients with diffuse or heterogeneous brain disorders and healthy controls. In this study, we obtained anatomical and functional data from patients with brain disorders where traditional methods have been insufficient to fully assess the condition. More specifically, we tested our method on mild traumatic brain injury, autism spectrum disorder, chemotherapy-induced cognitive impairment and chronic fatigue syndrome patients. Three major databases from the Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC) project were used to acquire large numbers of age matched healthy controls. Healthy control data was downloaded from the the Autism Brain Imaging Data Exchange (ABIDE), the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Human Connectome Project specifically matching our experimental design. In all of our studies, the voxel-wise rs-BOLD signal fractal dimension was calculated following a procedure described by Eke and Herman et al. 2000. This method was previously used to assess brain rs-BOLD signal in small mammals and humans. The method consists of estimating the Hurst exponent in the frequency domain using a power spectral density approach and refining the estimation in the time domain with de-trended fluctuation analysis and signal summation conversion methods. Voxel-wise fractal dimension (FD) was then calculated for every subject in the control and patient groups to create ROI-based Z-scores for each individual patient. Voxel-wise validation of FD normality across controls was studied and non-Gaussian voxels, determined using kurtosis and skewness calculations, were eliminated from subsequent analysis. To maintain a 95 % confidence level, only regions where Z-score values were at least 2 standard deviations away from the mean were included in the analysis. In the case of chronic fatigue patients and chemotherapy induced cognitive impairment, DTI analysis was added to also determine whether white matter abnormalities were also relevent. Similar Z-score analysis on DTI metrics was also performed. Brain microscopic networks, modeled as complex systems, become affected in diffuse brain disorders. Z-scoring of the fractal rs-BOLD frequency domain delineated patient-specific regional brain anomalies which correlated with patient-specific symptoms. This technique can be used alone, or in combination with DTI Z-scoring, to characterize a single patient without any need for group analysis, making it ideal for personalized diagnostics. / Thesis / Doctor of Philosophy (PhD)

<div><div><div><p>Head injuries in collision sports have been linked to long-term neurological disorders. High school collision sport athletes, a population vulnerable to head injuries, are at a greater risk of chronic damage. Various studies have indicated significant deviations in brain function due to the accumulation of repetitive low-level subconcussive impacts to the head without externally observable cognitive symptoms. The aim of this study was to investigate metabolic changes in asymptomatic collision sport athletes across time within their competition season and as a function of mechanical force to their head. For this purpose, Proton Magnetic Resonance Spectroscopy (MRS) was used as a tool to detect altered brain metabolism in high school collision sport athletes (football and soccer) without diagnosed concussion. Also, sensors were attached to each athletes head to collect the count and magnitude of head impacts during their games and practices. Transient neurometabolic alterations along with prolonged recovery were observed in collision sport athletes.</p><div><div><div><p><br></p><p>Multi-site studies are becoming important to increase statistical power, enhance generalizability, and to improve the likelihood of pooling relevant subgroups together activities which are otherwise limited by the availability of patients or funds at a single site. Even with harmonized imaging sequences, site-dependent variability can mask the advantages of these multi-site studies. The aim of this study was to assess multi-site reproducibility in resting-state functional connectivity fingerprints, and to improve identifiability of obtained functional connectomes. We evaluated individual fingerprints in test- retest visit pairs within and across two sites and present a generalized framework based on principal component analysis (PCA) to improve identifiability. The optimally reconstructed functional connectomes using PCA showed a substantial improvement in individual fingerprinting of the subjects within and across the two sites and test-retest visit pairs relative to the original data. Results demonstrate that the data-driven method presented in the study can improve identifiability in resting-state functional connectomes in multi-site studies.</p></div></div></div></div></div></div>

The NeuroTracker (NT), a computerized three-dimensional multiple object tracking (3D-MOT) training device, has potential benefits for concussion assessment and management, as well as maintenance of cognitive function. Accessing 3D technology is a limiting factor for 3D-MOT, so we assessed the performance of MOT training in 2D and 3D environments in both healthy and concussed individuals (8-91 years of age). The participants (n=86) who completed all ten training sessions over the three-month period, were assigned to one of three different studies: (1) an environment comparison (2D versus 3D), (2) an age comparison (youth, young adult, and older adult), or (3) a concussed population comparison (non-concussed, recently concussed, and prolonged concussed). In all studies, performance increased with training, indicating all individuals could increase perceptual cognitive function in all environments. Significant differences were apparent when 2D and 3D environments were compared, with participants in the 3D environment out performing participants in the 2D environment. Furthermore, switching from the 3D to the 2D environment was detrimental to learning performance. When comparing learning performance between different aged individuals, a linear regression demonstrated learning performance increased at a lesser rate with age(p<0.05). Concussed populations also demonstrated correlative trends when comparing learning performance, as well as initial NT scores. The longer an individual was suffering from concussion symptoms, the lower the initial NT score was, but the higher the rate of learning performance was through out training. Further investigation into attention, memory, and visual processing speeds in each population may help to better resolve the relationship between these domains and clarify if NT can serve as a means for concussion assessment and rehabilitation for individuals at any age in the future. / Graduate

No description available.

Symptoms of dizziness and imbalance are common sequelae following concussion and blast exposures that result in mild traumatic brain injury (mTBI), and these symptoms often last six months or longer. Most studies examining the effect of vestibular dysfunction on postural stability have used symptom scales or tests of vestibulo-ocular reflex (VOR) that measure horizontal semicircular canal (hSCC) function only. Vestibular loss, however, can occur in one or both labyrinths, in one or both branches of the vestibular nerve, and in one or more vestibular sensory end-organs. A prospective case-controlled design was used to determine the effect of mTBI and blast exposure on peripheral vestibular system function, postural stability, and gait. MANOVAs revealed significant differences between the control and mTBI and blast groups for cervical vestibular evoked myogenic potentials, sensory organization test, and dynamic gait index. These findings suggest that mTBI and blast affect the otolith organs, postural stability, and gait. The frequency of test abnormalities ranged from 22 to 71% with the most frequent abnormalities occurring on tests of balance and gait function. Vestibular test abnormalities occurred in 48% of individuals with mTBI and/or blast exposure. Specifically, abnormalities occurred more often in tests of otolith organ function than hSCC function.

Concussion affects the adolescent population in large numbers, primarily because of the popularity of team sports that are played in middle and high school. This adolescent age group is more susceptible to the adverse effects of concussion due to physiological immaturity, and recovery for this population takes longer than in adults. Speech-language pathologists, who are trained to treat cognitive-communication deficits, are present in the majority of school systems throughout the United States, and could be a useful resource to manage and treat students who incur concussion. However, speech-language pathologists historically have not treated students with concussion, and may not be receiving adequate education regarding concussion in graduate programs. This study sought to ascertain the education, training, and experience regarding concussion of speech-language pathologists in Texas secondary schools. Anonymous survey responses were collected via an Internet survey platform, yielding 49 respondents for the final data pool. The answers provided by these respondents indicate Texas speech-language pathologists are not yet receiving adequate concussion education and training. Respondents reported low confidence levels in several key areas of concussion knowledge, and doubt regarding the speech-language pathologist's role in managing concussion. Recommendations include concussion-targeted graduate school curriculum as an extension of traumatic brain injury curriculum, increased continuing education efforts by ASHA regarding concussion and the speech-language pathologist's role in treating concussion, and further advocacy by ASHA for speech-language pathologists to be part of concussion management teams based in schools. / text