INTRO: There is mounting evidence to suggest a causal link between mild traumatic brain injury (mTBI) and post traumatic epilepsy (PTE). Significant ranges in the methods and definitions of “mild” TBI, each with their own limitations, make drawing cohesive conclusions from the state of the literature difficult. However, this body of work attempts to compile the literature in order to better elucidate the relationship between these populations. Ultimately, I hope this source to be a useful reference for understanding the state of the research such that one can make critical considerations in the future design of methods to definitively improve the quality of work in this field. Meaningful improvements could radically improve the outcomes for the millions of people who suffer as a result of these injuries and their lasting implications. METHODS: PubMed searches used keywords: Traumatic Brain injury (mild), Epilepsy, Concussion, Loss of cortical inhibition, Post Traumatic Epilepsy. Combinations of terms including mTBI or PTE AND MRI, fMRI, DTI, MRS, Biomarkers, TMS, EEG, and pathology. RESULTS: Strong trends persist despite the limitation in consistency of terminology and methods. Relative risk scores between 1.5 and 2.2 percent have been established across multiple long-term studies across decades of research and millions of person years, a 2-3-fold change over the baseline incidence of epilepsy in the general population (0.7%; less than one in every 100). Preclinical studies in mice have recently shown progressive increased seizure susceptibility after repeated mTBI. Within the first three weeks after injury, Glutamate homeostasis is altered meaningfully. Increased neural excitability results as the balance between excitation and inhibition shifts in the brain. An increased Glu/GABA ratio has also been linked to dysfunction in GABAergic cell populations, including parvalbumin positive inhibitory interneurons (PVI). Oxidative stress, as measured by a decreased GSH/GSSG ratio, suggests a dysregulation in homeostatic processes than can outlive clinical symptoms. Animals also display a decreased latency to induced seizure by Pentelynetetrazole (PTZ) a potent GABA receptor antagonist. Six weeks after injury, these mice have been shown to display; decreased GABA driving an increased Glu/GABA ratio, decreased EEG gamma power, and prominent signs of gliosis involving both astrocytes and microglia. Clinical investigations into the biology of this injury, utilizing a wide range of techniques, point to a loss of cortical inhibitory tone, an early hallmark of PTE. TMS findings of both reduced resting motor threshold and a shorter cortical silent period suggest a loss of cortical inhibitory tone likely shifting the excitation/inhibition balance. Signs of microstructural damage and altered cell permeability point to a disruption in chemical gradients which leads to greater functional deficits, as the parameters for normal cell function are no longer maintained. Changes in function and metabolism have been shown to outlast many of the behavioral and acute clinical symptoms suggesting a slow development but long duration of this insidious process. CONCLUSION: Mechanisms that link mTBI to PTE include a loss of cortical inhibition, increased oxidative stress and gliosis which over time increases Glu/GABA ratio, in turn increasing the likelihood of developing epilepsy. Although the relationship between mTBI and PTE has been suggested before through epidemiological studies, there is now emerging biochemical evidence to better describe this connection. Due to the high incidence of mTBI, any small increase in risk to develop PTE pursuant to concussion will affect millions of lives. With this new evidence, treatments can be designed to halt the progression and alleviate symptoms for those afflicted. The investigation of the biological mechanisms that link concussion and epilepsy is a critical step in developing treatment strategies and prophylaxis that could prove to be crucial for so many.

Concussions remain a serious public health concern, with approximately 1.6 million to 3 million sport and recreational traumatic and brain injuries occurring every year in the United States. Most research on concussions has been conducted on male athletes, specifically, football players. However, female sport participation has steadily increased over the past decade. Recent studies suggest that the incidence of and recovery from sport-related concussion varies between male and female athletes, with women having a higher risk of sustaining a concussion and taking a longer time to recover than men. As a result, this article addresses the role of gender in the assessment and management of sport-related concussion.

Background: The ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) neurocognitive testing battery is a popular assessment tool used for concussion management. The stability of the baseline neurocognitive assessment is important for accurate comparisons between postconcussion and baseline neurocognitive performance. Psychometric properties of the recently released online version of ImPACT have yet to be established; therefore, research evaluating the reliability of this measure is warranted.Purpose: The authors investigated the 1-year test-retest reliability of the ImPACT online version in a sample of high school athletes.Study Design: Case series; Level of evidence, 4Methods: A total of 369 varsity high school athletes completed 2 mandatory preseason baseline cognitive assessments approximately 1 year apart as required by their respective athletics program. No diagnosed concussion occurred between assessments.Results: Intraclass correlation coefficients (ICCs) for ImPACT online indicated that motor processing speed (.85) was the most stable composite score, followed by reaction time (.76), visual memory (.70), and verbal memory (.62). Unbiased estimates of reliability were consistent with ICCs: motor processing speed (.85), reaction time (.76), visual memory (.71), and verbal memory (.62).Conclusion: The online ImPACT baseline is a stable measure of neurocognitive performance across a 1-year time period for high school athletes. These reliability data for online ImPACT are higher than the 2-year ICCs previously reported from the desktop version.Clinical Relevance: It is recommended that the ImPACT baseline assessment (both desktop and online) continue to be updated every 2 years. The online version of ImPACT appears to be a stable measure of neurocognitive performance over a 1-year period, and systematic evaluation of its stability over a 2-year period is warranted.

The long-term effects of repetitive head impacts are a growing concern. Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that is associated with repetitive head impacts and is characterized by distinct neuropathological changes. Other risk factors of developing CTE are still unknown but may include age, genetics, age of first exposure to sports and type of sport. The only way to diagnose CTE is with a post-mortem analysis. Current research is focused on diagnosing CTE during life; efforts are turning towards developing a clinically diagnosable syndrome that is related to CTE prognosis. Common symptoms reported from retrospective analyses of CTE confirmed cases include cognitive difficulties as well as mood and behavior symptoms like depression and impulsivity. The goal of the present study was to define the clinical presentation of a diverse group of former athletes in an effort to categorize a clinical presentation of individuals with various head impact exposure. The individuals in the sample included contact and non-contact sport athletes, both male and female, ranging from 19 to 86 years of age. The data was based on a larger study, the Longitudinal Examination to Gather Evidence of Neurodegenerative Disease (LEGEND). In a sample of 592 participants from this study, cluster analyses identified five discrete groups of individuals based on their symptom profile. These included Asymptomatic, Mildly symptomatic, Mood symptoms, Behavior symptoms and Highly symptomatic groups. Between the groups, there was no difference in age of participants. There was no prevalence of a certain sport in any of the clusters. Additionally, there was no significant finding regarding estimated number of head impacts and symptomatology in football players. Results showed an effect of cognitive reserve, measured by years of education. Participants in the Asymptomatic group had significantly more education. This implies that years of education may be a risk factor for decreasing one’s ability to cope with neuropathology. Further research needs to be done on the connection between symptomatology and neuropathological diagnosis.

Concussion management is changing. Recent years have marked a sea change, with the former rest-is-best approach being supplanted by an exercise-is-medicine mindset. Despite this, important questions remain unanswered in the pediatric exercise-concussion literature. The overarching aim of this thesis was to examine the effects of exercise on outcomes beyond concussion symptoms, and build our understanding of the relationship between pediatric concussion and physical activity. Four studies were performed to this end. First, per a systematic review, we found that randomized trials on the effects of exercise on neuroimaging and cognitive outcomes remain limited. Studies suggest that exercise may improve brain structure and function post-concussion, while data with respect to cognitive outcome were mixed. Second, we provided the first evidence that the functional neuropathology of pediatric concussion differs by sex at 1 month post-injury, with females demonstrating impairment not observed in males. Namely, only females with concussion showed patterns of both hyper-connectivity (between the lateral pre-frontal cortex & inferior frontal gyrus, lateral pre-frontal cortex & lateral occipital cortex, and the posterior cingulate cortex & cerebellum; all p-corrected <0.05) and hypo-connectivity (between the anterior cingulate cortex & precuneus, anterior cingulate cortex & cingulate gyrus, and posterior cingulate cortex & paracingulate gyrus; all p-corrected <0.05). Third, we provided the first accelerometer-based characterization of physical activity and sedentary time in children with concussion in comparison to 1:1 matched healthy controls. Relative to healthy controls, children with concussion were more sedentary, with a mean difference [MD] of 38.3 minutes/day (95% confidence interval [CI] 11.2 to 65.4, p<0.01), and they also performed less light (MD -19.5 minutes/day, CI -5.3 to -33.7, p<0.01), moderate (MD -9.8 minutes/day, CI -5.7 to -13.8, p<0.001) and vigorous physical activity (MD -12.0, CI -6.9 to -17.2, p<0.001); greater physical activity deficits were observed in females with concussion. Fourth, per the first study to employ both accelerometry and functional neuroimaging in pediatric concussion, we found that intra-network connectivity of the default mode network was associated with subsequent accelerometer-measured light (F(2, 11) = 7.053, p = 0.011, Ra2 = 0.562; β = 0.469), moderate (F(2, 11) = 6.159, p = 0.016, Ra2 = 0.528; β = 0.725), and vigorous (F(2, 11) = 10.855, p = 0.002, Ra2 = 0.664; β = 0.792) physical activity. This study provides the insight into a potential link between brain activity and physical activity in pediatric concussion. The next wave of exercise and physical activity research in concussion needs to move beyond symptom studies, employ sex-specific analyses, understand the impact of exercise on brain function, and consider interventions that increase habitual physical activity. Doing so is necessary for exercise to become medicine for concussion patients. / Thesis / Doctor of Philosophy (PhD) / Until a few years ago, the advice children received after a concussion (or mild brain injury) was to rest until they no longer had symptoms. But the way concussions are being treated is changing. Scientists have found that exercising soon after a concussion can lessen symptoms. It is no longer thought that rest-is-best. Instead, it is now believed that exercise-is-medicine. But there are still important questions about the role of exercise after a concussion that have not been answered. The four studies in this thesis had the goal of answering some of those questions. In the first study, we found that while exercise improves symptoms after a concussion, we know less about how it impacts the brain and our ability to think. From the second study, we learned that a concussion impacts the brains of boys and girls in different ways, and that girls may have longer lasting brain changes after a concussion than boys. Our third study showed that after a concussion, girls take part in less physical activity than boys throughout the day. The fourth study suggests that there may be a link between brain activity and physical activity in children with a concussion. This thesis adds to our knowledge of the role of exercise in concussion. It also raises some important questions that should be answered by new studies in the near future.

No description available.

Concussion is a life-altering injury that can affect people of all ages. Event-related potentials (ERPs) extracted from electroencephalography (EEG) have proven sensitive to concussion-induced cognitive deficits. The MMN, P3a, P3b, and N2b are some ERP components of interest, assessing automatic attention, attentional resource allocation, working memory, and inhibitory executive function, respectively. These ERPs can assess some common symptoms associated with concussion at a level that cannot be attained using self-report. A reduced amplitude and potentially delayed latency of the P3a and P3b is a well-replicated result in concussion research. Furthermore, recent research suggests that an alteration in amplitude of earlier peaks such as the N2b and MMN might represent an irreversible change in cognitive processing that tends to occur in the chronic stages of concussion. Many of these studies have focused on athletes, however little research has evaluated the cognitive effects of sustaining numerous blows to the head that do not result in a clinical diagnosis of concussion, as is the case for many athletes in contact sports. These blows are often referred to as subconcussive impacts. The present study examined the cognitive and neurophysiological effects of subconcussive impacts on collegiate contact-sport athletes and compared them to noncontact athletes. The athletes completed questionnaires to evaluate their health and athletic history, as well as estimates of exposure to subconcussive impacts such as position and playing time, prior to participating in three paradigms meant to assess various cognitive processes during an EEG recording. Across two experiments we demonstrated that subconcussive impacts within a season of play can result in alterations in neurophysiological markers of cognitive health. Our findings also reveal that continued involvement in contact sports can have serious implications in one’s automatic attention, resource allocation, and working memory as demonstrated by reduced ERP amplitudes in contact as compared to non-contact athletes. / Thesis / Master of Science (MSc) / A concussion is a devastating injury that can greatly affect how an individual functions in their day-to-day life. Concussions are often discussed in the context of contact sports because of these athletes’ exposure to repeated head impacts. That said, another cause for concern is the effects of head impacts that do not result in a concussion per se – these are known as subconcussive impacts. A brain imaging technique known as electroencephalography (EEG) involves recording brain activity from sensors on the head. Conducting this recording while individuals perform tasks known to evaluate brain function offers an opportunity to assess symptoms rather than relying on a patient’s own, subjective report of their experiences. The present study investigated the use of EEG in evaluating the effects of subconcussive impacts in collegiate athletes and found that repeated head impacts can reduce cognitive health, even if they do not result in a diagnosis of concussion.

As many as 1.9 million sports-related concussions occur annually in youth sports in the United States (U.S.). Often considered a transient injury, research has begun to relate sports-related concussions to long-term neurodegeneration. Youth athletes are considered to be more vulnerable to concussion than their adult counterparts. The research presented in this dissertation was aimed at promoting player safety in youth football as it relates to concussion. Balance dysfunction is often cited as one of the most common symptoms associated with a concussion. Several postural control assessments were assessed in order to develop a youth-specific testing protocol. A cognitive, dual-task assessment was presented for clinician use in the management of sports-related concussion. On-field data collected from youth football players wearing instrumented helmets allowed for characterization of the biomechanics of head impacts and concussions for this population. A youth concussion risk function was developed using head impact data collected from youth football players with medically diagnosed concussions. The proposed testing standard for youth football helmets was assessed in the laboratory and related to on-field head impact data to determine how representative the standard is of youth football head impacts. Helmet safety standards and certifications operate on a pass-fail threshold that does not allow consumers to weigh the relative performance of helmets. A modification of the Summation of Tests for the Analysis of Risk (STAR) evaluation system was developed for youth football helmets. Data presented in this dissertation have direct application to the development of future helmet safety standards and potentially other safety applications as well. / Doctor of Philosophy / As many as 1.9 million sports-related concussions occur annually in youth sports in the United States (U.S.). Often considered a short-term injury, research has begun to relate sports-related concussions to long-term breakdowns in neurological processes. Youth athletes are considered to be more vulnerable to concussion than their adult counterparts. The research presented in this dissertation was aimed at informing player safety in youth football as it relates to concussion. Abnormal balance is often cited as one of the most common symptoms associated with a concussion. Several balance assessments were assessed in order to develop a youth-specific testing protocol. An assessment involving quiet standing while being subjected to a cognitive task was presented for clinician use in the management of sports-related concussion. On-field data collected from youth football players wearing instrumented helmets allowed for characterization of the biomechanics of head impacts and concussions for this youth population. A youth concussion risk function was developed that related linear and rotational head acceleration to risk of concussion. The proposed testing standard for youth football helmets was assessed in the laboratory and observed to assess the most severe head impacts a youth player may experience during participation in football. A modification of the Summation of Tests for the Analysis of Risk (STAR) evaluation system was developed for youth football helmets in order to give consumers more information about helmet performance beyond the pass-fail criteria of the helmet standards. Data presented in this dissertation have direct application to the development of future helmet safety standards and potentially other safety applications as well.

The research presented in this thesis focuses on head impact exposure in youth football. The on-field portion of this research investigated high magnitude head impacts that youth football players experience in games and practices. With previously validated data collection methods, linear and rotational head accelerations from head impacts were collected. Over the course of two seasons, 79 total player-seasons resulted in over 13,000 impacts. A small subset of these, 979 impacts exceeding 40 g, represented the focus of this research as these impacts pose the greatest risk of injury to individuals. Some tackling drills in practice were found to have higher acceleration severities than those observed in games. How practice activities are conducted also contributes towards the overall high magnitude head impact exposure for practice, not just the practice drill itself. Within games, players who are running backs and linebackers played most frequently and experienced higher magnitude impacts more often than their teammates. Data were also collected from all players off the field. Each player completed balance assessments at the beginning and end of the season to allow for comparison, even in absence of a clinically-diagnosed concussion. Current balance assessments were observed to fall short for detecting postural control differences in this youth population. Modifications to these assessments were recommended that might allow for further insights. Research presented in this thesis will inform youth football organizations as they continue to develop strategies to enhance player safety and mitigate head impact exposure. / Master of Science

While there has been ample research examining the relationship between an acute concussion on immediate neuropsychological performance, very little research has examined the relationship between lifetime concussion history with current neuropsychological performance. We collected preseason neuropsychological test performance (ImPACT) and a detailed lifetime concussion history questionnaire from 71 UCF football players. Stepwise linear regressions were conducted for each of the five ImPACT domain scores for the 18 participants that reported at least one lifetime concussion. The regressions used the following four concussion history predictors: total number of lifetime concussions, length of time between last concussion and lmPACT testing, severity of worst concussion, and severity of most recent concussion. Results revealed that only one ImpACT domain score had at least one predictor enter the model. For the domain of visual memory, the predictor of length of time between last concussion and ImPACT testing entered the model (and only that predictor),P = 4.07, t(l7) = 2.78,p = .01, R1 = .33, as a shorter length of time between the last concussion and the preseason testing related to lower performance on the visual memory tests. Many athletes and clinicians assume that the cognitive effects of a concussion are relatively brief in duration. However, the results of this study suggest that, at least for visual memory, these effects may last for several years following a concussion. The correlational design of this study precludes drawing conclusions about the causal direction of this relationship, but future longitudinal research may be able to clarify this important preliminary finding.