There is increasing evidence that repeat mild traumatic brain injury (rmTBI) may result in cumulative and long-term symptoms, more pronounced behavioural deficits, and neurodegeneration. Children have a greater susceptibility to head injury and represent a significant at risk population for rmTBI, especially those that participate in contact sports. Despite this, there is a paucity of data on rmTBI pathophysiology in the juvenile brain. The current study utilizes a novel awake closed head injury (ACHI) model to deliver repeat injuries to fully conscious juvenile rats. The ACHI model avoids the potential confounds of anaesthesia, and facilitates the assessment of neurological function immediately after each impact. Results indicate that the ACHI model produces acute neurological deficits after each impact, and that repeat injury worsens outcomes. Behavioural testing identified transient anxiety-like behaviour and motor impairment in response to rmTBI. The functional impairments and affective behaviour were in the absence of tau protein pathology. This study represents the first investigation of the consequences of rmTBI on the juvenile brain using an awake model of brain injury. / Graduate

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).

abstract: Adults with a history of traumatic brain injury (TBI) often show deficits in executive functioning, which include the ability to inhibit, switch, and attend to task relevant information. These abilities are also essential for language processing in bilinguals, who constantly inhibit and switch between languages. Currently, there is no data regarding the effect of TBI on executive function and language processing in bilinguals. This study used behavioral and eye-tracking measures to examine the effect of mild traumatic brain injury (mTBI) on executive function and language processing in Spanish-English bilinguals. In Experiment 1, thirty-nine healthy bilinguals completed a variety of executive function and language processing tasks. The primary executive function and language processing tasks were paired with a cognitive load task intended to simulate mTBI. In Experiment 2, twenty-two bilinguals with a history of mTBI and twenty healthy control bilinguals completed the same executive function measures and language processing tasks. The results revealed that bilinguals with a history of mTBI show deficits in specific executive functions and have higher rates of language processing deficits than healthy control bilinguals. Additionally, behavioral and eye-tracking data suggest that these language processing deficits are related to underlying executive function abilities. This study also identified a subset of bilinguals who may be at the greater risk of language processing deficits following mTBI. The findings of this study have a direct impact on the identification of executive function deficits and language processing deficits in bilinguals with a history mTBI. / Dissertation/Thesis / Doctoral Dissertation Speech and Hearing Science 2015

A small subset of individuals that have experienced mild traumatic brain injury (mTBI) may experience persistent cognitive deficits more than a year following the head injury. Neuroimaging studies reveal structural and functional changes in frontal areas of the brain, exacerbated when loss of consciousness is experienced, and indicate that these changes may be progressive in nature for some people. Social support and social participation have, however, been suggested to confer cognitive reserve - neurocognitive protection against cognitive decline. Analyses were run on Canadian Longitudinal Study on Aging (CLSA) neuropsychological data, consisting of individuals who experienced mTBI with loss of consciousness (n = 536 for less than 1 minute, and n = 435 for unconsciousness between 1 and 20 minutes) more than a year prior, and 13,163 no-head injury comparisons. These same individuals were re-assessed three years later. The results presented in this thesis suggest that at a year or more after a single mTBI with loss of consciousness, a small subset of individuals are more likely to be impaired on prospective memory and other executive functioning tasks, relative to comparisons. In addition, when examined at three-year follow-up, those who experienced mTBI with longer duration of unconsciousness were more likely to exhibit cognitive decline relative to those who experienced less unconsciousness or comparisons. Moreover, greater social participation over the past year, and more perceived social support were predictive of lessened cognitive deterioration in those individuals.

Researchers studying the long-term cognitive sequelae of mild traumatic brain injury (mTBI) have produced disparate results. Some studies have shown little to no long-term cognitive effects while others have shown that persistent cognitive sequelae continue to affect a subgroup of patients. Meta-analysis has been used to try to integrate these contrasting results to foster a coherent understanding of the cognitive outcomes following mTBI. However, previous meta-analyses of long-term cognitive sequelae have used studies from a period of mTBI research where methodological rigor has been called into question (Carroll, Cassidy, Holm, Kraus, & Coronado, 2004). Using studies from this period, meta-analysts found little to no effect for long-term cognitive sequelae after mTBI: g = 0.07, d = 0.12 (Binder, Rohling, & Larrabee, 1997), g = 0.11(Frencham, Fox, & Mayberry, 2005), and d = -0.07 (Rohling et al., 2011). The present meta-analysis was conducted to address problems with methodological rigor in the studies used in these previous meta-analyses and address differences in meta-analytic methodology (Pertab, James, & Bigler, 2009). Studies published between January 2003 and August 2010 were rated using the 4-tiered American Academy Neurology (AAN) guidelines for methodological rigor to ensure homogeneity and the methodological rigor of included studies. Seven studies were identified that met criteria for a rating of I or II and five met criteria for the lower ratings of III or IV. When studies of all ratings were combined, a significant effect of g = 0.45 was observed. When only studies rated I and II were combined, a significant effect of g = 0.52 was observed while a significant effect of g = 0.38 was observed when only studies rated III and IV were combined. These effect sizes for long-term cognitive sequelae are much larger than those found in previous meta-analyses. Based on these results, it is likely that methodological rigor and/or heterogeneity amongst included studies can impact meta-analytic effect sizes associated with long-term cognitive sequelae following mTBI. However, analyses did not show that more rigorous studies (i.e., those rated I or II) had significantly higher effect sizes than less rigorous studies (i.e., those rated III or IV), t(10) = .636, p = .845. This non-significant finding may be a result of the analysis being underpowered given the small k. Significant effects for neuropsychological domain were also observed and are reported. Additionally, a conceptual critique of mTBI is made with recommendations for future development of the rating system that Cappa, Conger, and Conger (2011) have put forth for objectively rating the methodological rigor of neuropsychological studies. Concerns are addressed related to the mTBI literature in the areas of mTBI definition, definition of cognitive impairment, problems with the constructs of post-concussion syndrome (PCS) and persistent post-concussion symptoms (PPCS), heterogeneity of outcome measurement, and unaccounted for variables.

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Between 1.6 and 3.8 million sports-related concussions are sustained by persons living in the United States annually. While sports-related concussion was once considered to only result in immediate neurocognitive impairment and symptoms that are transient in nature, recent research has correlated long-term neurodegenerative effects with a history of sports-related concussion. Increased awareness and current media attention have contributed to concussions becoming a primary health concern. Although much research has been performed investigating the biomechanics of concussion, little is understood about the biomechanics that cause concussion in humans. The research presented in this dissertation investigates human tolerance to head acceleration using methods that pair biomechanical data collected from human volunteers with clinical data. Head impact exposure and injury risk are quantified and presented. In contrast to the publicly available data on the safety of automobiles, consumers have no analytical mechanism to evaluate the protective performance of football helmets. With this in mind, the Summation of Tests for the Analysis of Risk (STAR) evaluation system was developed to evaluate the impact performance of footballs helmets and provide consumers with information about helmet safety. The STAR evaluation system was designed using real world data that relate impact exposure to injury risk. / Ph. D.

Background and aims: The provenance of post-concussion symptoms (PCS) and post-traumatic stress (PTSD) after mild traumatic brain injury (mTBI) is controversial. This thesis investigated factors influencing these two conditions separately, as well as the interplay between PCS and PTSD, in individuals with mTBI and a control sample without mTBI (orthopaedic injuries). Method: Consecutive adult attendees of an Emergency Department with mTBI or orthopaedic injury were prospectively recruited and completed the Rivermead Post-concussion Questionnaire (RPQ) and Trauma Screening Questionnaire (TSQ) for PTSD at two weeks (T1) and three months (T2) post-injury. The sample at T1 consisted of 34 with complicated mTBI, 76 with uncomplicated mTBI and 47 with orthopaedic injury, and 18 with complicated mTBI, 43 with uncomplicated mTBI and 33 orthopaedic controls at T2. Results: Although there were no differences in overall PCS symptomology between groups, a subset of PCS symptoms (headaches, dizziness and nausea) was found to be specific to mTBI at both time points. These symptoms are proposed to have a neurological basis, as opposed to a psychological basis. PTSD interacted with PCS, particularly in mTBI, such that PTSD was associated with greater “neurogenic” and “psychogenic” symptomology in this group, but only a moderate increase in psychogenic symptoms for controls. A model of the influence of PTSD on PCS is presented. PTSD was influenced by poor memory quality for the traumatic event and attribution of blame to others, but not by mTBI. Discussion and conclusions: Though mTBI may set the scene for at least neurogenic symptoms of PCS to occur, psychological mechanisms, particularly PTSD, have a significant role in the persistence of PCS. Our findings suggest the need for a clear story and sense of meaning for a traumatic event for good recovery from PTSD. Taken together, the results suggest that psychological interventions, particularly aimed at PTSD, may be most effective after mTBI.

National concern over traumatic brain injury (TBI) is growing rapidly. Recent focus is on mild TBI (mTBI), which is the most prevalent injury level in both civilian and military demographics. A preeminent sequelae of mTBI is cognitive network disruption. Advanced neuroimaging of mTBI victims supports this premise, revealing alterations in activation and structure-function of excitatory and inhibitory neuronal systems, which are essential for network processing. However, clinical neuroimaging cannot resolve the cellular and molecular substrates underlying such changes. Therefore, to understand the full scope of mTBI-induced alterations it is necessary to study cortical networks on the microscopic level, where neurons form local networks that are the fundamental computational modules supporting cognition. Recently, in a well-controlled animal model of mTBI, we demonstrated in the excitatory pyramidal neuron system, isolated diffuse axonal injury (DAI), in concert with electrophysiological abnormalities in nearby intact (non-DAI) neurons. These findings were consistent with altered axon initial segment (AIS) intrinsic activity functionally associated with structural plasticity, and/or disturbances in extrinsic systems related to parvalbumin (PV)-expressing interneurons that form GABAergic synapses along the pyramidal neuron perisomatic/AIS domains. The AIS and perisomatic GABAergic synapses are domains critical for regulating neuronal activity and E-I balance. In this dissertation, we focus on the neocortical excitatory pyramidal neuron/inhibitory PV+ interneuron local network following mTBI. Our central hypothesis is that mTBI disrupts neuronal network structure and function causing imbalance of excitatory and inhibitory systems. To address this hypothesis we exploited transgenic and cre/lox mouse models of mTBI, employing approaches that couple state-of-the-art bioimaging with electrophysiology to determine the structural- functional alterations of excitatory and inhibitory systems in the neocortex.