Indiana University-Purdue University Indianapolis (IUPUI) / In eukaryotes, genetic information is encoded by DNA, transcribed to precursor messenger RNA (pre-mRNA), processed into mature messenger RNA (mRNA), and translated into functional proteins. Splicing of pre-mRNA is an important epigenetic process that alters the function of proteins through modifying the exon structure of mature mRNA transcripts and is known to greatly contribute to diversity of the human proteome. The vast majority of human genes are expressed through multiple transcript isoforms. Expression of genes through splicing of pre-mRNA plays crucial roles in cellular development, identity, and processes. Both the identity of genes selected for transcription and the specific transcript isoforms that are expressed are essential for normal cellular function. Deviations in gene expression or isoform proportion can be an indication or the cause of disease. RNA sequencing (RNAseq) is a high-throughput next-generation sequencing technology that allows for the interrogation of gene expression on a massive scale. RNAseq generates short sequences that reflect pieces of mRNAs present in a sample. RNAseq can therefore be used to explore differences in gene expression, reveal transcript isoform identities and compare changes in isoform proportions. In this dissertation, I design and apply advanced analysis techniques to RNAseq, phenotypic and drug response data to investigate disease mechanisms and drug sensitivity. Research Goals: The work described in this dissertation accomplishes 4 aims. Aim 1) Evaluate the gene expression signature of concussion in collegiate athletes and identify potential biomarkers for response and recovery. Aim 2) Implement a machine-learning algorithm to determine if splicing can predict drug response in cancer cell lines. Aim 3) Design a fast, scalable method to identify differentially spliced events related to cancer drug response. Aim 4) Construct a drug-splicing network and use a systems biology approach to search for similarities in underlying splicing events.

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PURPOSE: Sport-related concussions and migraine are both national healthcare concerns that cost billions of dollars in economic burden annually in the United States as well as cause hardship on the individual. More than 539,600 student-athletes in the United States will be directly affected by both comorbidities each year, and the health care providers that care for them will have to make decisions based on both conditions. How healthcare providers are educated on these two conditions, their attitudes in diagnosing and managing these conditions, and beliefs about their role has not been established (aim 1). Due to a common pathophysiology, pre-morbid migraine has been identified as a risk factor for worse outcomes after an individual sustains concussion. However, the impact of these conditions and prescribed medications on commonly used baseline assessments has not been identified (aims 2 and 3). This may have implications in student-athlete referral to other healthcare professionals, in interpretation of test results, and in management of post-injury cases. Many individuals diagnosed with migraine take daily preventative medication (e.g., topiramate); however, these medications have been identified to cause cognitive impairment but the deficit in the collegiate student athlete and on the baseline concussion assessment is unknown (aim 3). Since cognitive exams make up a large portion of the concussion baseline assessment, identifying any real or perceived deficits in these tests may also allow healthcare providers to make decisions for test interpretation for these individuals. PARTICIPANTS: For aim 1, certified athletic trainers from the National Athletic Trainers’ Association and targeted social media groups were recruited to take a novel electronic survey. A total of 576 individuals that completed more than 90% of the survey were included in the final analysis. Student-athletes participating in club and varsity sports at Temple University undergoing routine baseline concussion assessments were recruited to have their data included for aims 2 and 3 (non-migraine = 387, migraine = 33, missing migraine status = 137). METHODS: The survey for aim 1 consisted of 7 subgroups of questions: demographics, concussion, migraine, and comorbid knowledge and atttitudes and beliefs. Questions mainly consisted of true/false and likert-style questions. For aims 2 and 3, student-atheltes completed their routine annual concussion baseline assessment. This consisted of a health history questionnaire, symptom checklist, Hospital Anxiety and Depression Scale, cognitive assessments, postural control test, and vestibular/oculomotor exams. Indiviudals that self-reported a history of migraine were included in aim 3 for analysis of medication use. RESULTS: For aim 1, 61% of respondents had a masters degree and 40% worked in middle or high school athletics. Over 94% of respondents previously reported receiving concussion education, compared to only 40.5% for migraine education. Respondents were able to correctly identify an average of 74% of concussion signs and symptoms and 66% of migraine signs and symptoms. Collegiate and split positions were associated with more negative concussion attitudes and beliefs. A lack of previous concussion or migraine education was associated with more negative attitudes and beliefs. For each year clinically practicing, attitude and belief scores were slightly more positive (β = 0.03 – 0.70, p < 0.001). Females also generally had more positive attitudes and beliefs across outcomes (β = 1.09 – 2.61, p < 0.001). A total of 577 student-athletes were included in aims 2 and 3. Having migraine was associated with 2.36 more symptoms (p = 0.008) and a 5.20 higher severity score (p = 0.005). Migraine was also associated with a 5.58 higher odds of a slower reading time on the King-Devick (p < 0.01). From ImPACT, having migraine decreased visual memory composite by 9.97-points (p = 0.02) and visual motor composite score by 3.89-points (p = 0.07). Of the 33 student-athletes with migraine, 15 were taking a prescription medication, 3 were taking an over-the-counter medication or supplement, and 7 were taking both. None of the athletes were taking a daily preventative medicaton for migraine. The median Migraine Disability Assessment score was 4.5, indicating only little or no disability. The Brief Disability Questionniare showed no significant difference between those with and without migraine (Kruskall-Wallis (1) = 0.4, p = 0.50). Finally, there was high provider trust as measured with the modified Patient-Doctor Relationship Questionniare, and no significant difference between those with and without migraine (Kruskall-Wallis (1) = 1.59, p = 0.21). CONCLUSION: This was one of the first studies to identify athletic trainer knowledge, attitudes and beliefs surrounding concussion and migraine. Idenitfying groups with decreased atttitudes and beliefs can be used for targeted programming and ensuring these athletic trainers have support to increase knowledge and attitudes and beliefs for more positive patient outcomes. This study also determined that migraine affects some aspects of baseline concussion assesments. This can be used by clinicians during test interpretation for patient care. These student-athletes had low measures of disability and high levels of provider trust, key components for individuals with migraine to receive appropriate care. Concussion and migraine are significant healthcare concerns present in populations seen by athletic trainers. Future studies exploring post-concussion migraine effects and medication over the course of collegiate career should be considered. Adequate knowledge and positive attitudes and beliefs would be beneficial in ensuring appropriate medical care given to individuals experiencing these conditions. / Kinesiology

Introduction: Concussions in American Football are of a major concern due to highly reported injury rates. The importance of properly designed helmets have shown effect in reducing the risk of injuries, such as skull fractures. However, they are not as effective in reducing the risk of concussion. Helmets designed are required to pass standards and regulations for them to be allowed within the football leagues. The current test methods evaluate linear impacts, but lack evaluations of oblique impacts which are believed to cause concussions. Several test methods have been suggested, but little is known regarding how they compare. Objective: The purpose of this study was to compare three different test methods for evaluating helmet performance, utilizing finite element simulation. Three different helmet models were used for comparison, evaluating head kinematics. The helmet models were additionally ranked from best to worst based on their performances. Method: Three test methods, linear impactor, 45° angled linear impactor, and a drop test onto a 45° angled plate were simulated with three different open source helmet models. Simulations were conducted with one impact velocity at three impact locations. The influence of the interaction between helmet and head was also evaluated by altering the friction coefficient. Results: The test methods showed different results depending on helmet models, impact locations, and kinematics evaluated. Similarly, rankings of the helmets were varied based on methods and impact location. Little difference was observed after lowering the friction coefficient in majority of cases. The linear and angular acceleration for the drop side impact were mostly affected. Conclusion: Further evaluations of the test methods and comparison to real impacts is required to evaluate what method resembles head impacts best. Lowered friction coefficient had an effect for the drop impacts, but minor effect for other test methods

Compromised validity of test data due to exaggeration or fabrication of cognitive deficits inhibits the capacity to establish appropriate conclusions and recommendations in neuropsychological examinations. Detection of feigned neurocognitive impairment presents a formidable challenge, particularly for evaluations involving possibilities of significant secondary gain. Among specific populations examined in this domain, litigating mild traumatic brain injury (mTBI) samples are among the most researched. One subpopulation with potential to contribute significantly to this body of literature is that of retired athletes undergoing fixed-battery neuropsychological evaluations within an assessment program. Given the considerable prevalence of concussions sustained by athletes in this sport and the substantial monetary incentives within this program, a unique opportunity exists to establish rates of feigning within this population to be compared to similar forensic mTBI samples. Further, a fixed battery with multiple validity tests (VT) offers a chance to evaluate the classification accuracy of an aggregated VT failure paradigm, as uncertainty abounds regarding the optimal approach to the recommended use of multiple VTs for effort assessment. The current study seeks to examine rates of feigned neurocognitive impairment in this population, demonstrate prediction accuracy equivalence between models based on aggregated VT failures and logistic regression, and compare classification performance of various individual VTs.

Bakgrund: Risken att få hjärnskakning är högst hos individer som deltar i kollionsidrotter. Det uppskattas att cirka 1,6 till 3,8 miljoner sport relaterade milda traumatiska hjärnskador/hjärnskakningar uppstår årligen bland idrottare i USA, de flesta inom amerikansk fotboll. Hjärnskakning är en skada som rapporteras frekvent inom rugby och det är idag den vanligaste skadan inom rugby i England med gradvis ökning av incidens. De flesta sportrelaterade hjärnskakningar är av mindre allvarlig karaktär och de flesta idrottare återhämtar sig inom några dagar eller veckor men det finns en mindre grupp som utvecklar långvariga progressiva symptom framför allt vid upprepade hjärnskakningar och en del utvecklar kronisk traumatisk encefalopati (CTE). Syfte: Sammanställa och kritiskt granska vetenskaplig litteratur som beskriver hjärnskakning inom kollisionsidrotterna amerikansk fotboll och rugby med avseende på prevalens, behandling och rehabilitering samt prevention. Syftet är också att presentera rekommendationer utifrån aktuell litteratur, speciellt med avseende på riktlinjer för rehabilitering efter hjärnskakning. Metod: Studien har genomförts som en systematisk litteraturöversikt. Artiklar har sökts i databaserna PubMed och PEDro under februari 2023 från åren 2010-2023. Artiklar har även sökts i framtagna artiklars referenslistor. Studiernas metodologiska kvalitet har bedömts enligt granskningsmall som används av statens beredning för medicinsk och social utvärdering (SBU). Det internationella GRADE-systemet (Grading of Recommendations, Assesment, Development and Evaluation) har använts för att säkerställa tillförlitligheten (evidensstyrkan) i de inkluderade studierna. Resultat: Det slutliga resultatet inkluderar tio studier. Utrustningens effekt med avseende på incidens av hjärnskakning visar inte något entydigt svar. Signifikant minskat antal hjärnskakningar på träning i samband med begränsning av fullkontakt träning ses. Kombinerad nackbehandling/rehabilitering och vestibulär rehabilitering leder till att signifikant fler får medicinskt godkännande för återgång i idrott. Preventiva rörelsekontrollprogram medför en tydlig minskning av hjärnskakningar och preventivt synträningsprogram resulterar i signifikant minskad incidens av hjärnskakningar. Konklusion och rekommendation: Initialt rekommenderas att följa de rekommendationer som hjärntrappan påvisar och vid eventuella kvarvarande symptom därefter rekommenderas kombinerad nackbehandling och rehabilitering tillsammans med vestibulär rehabilitering. De mest effektiva preventiva åtgärderna är rörelsekontrollprogram och synträningsprogram som minskar incidensen av hjärnskakningar signifikant.

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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Concussions impact the cognitive abilities and emotional wellbeing of adolescents. More specifically, adolescents exhibit signs of executive dysfunction and depressive symptoms following concussion. Evidence suggests a link between cognitive performance and depressive symptoms in concussed populations; however, concussion research has focused mostly on cognitive deficits and emotional dysregulation in singularity, rather than as an integrated system. Therefore, the purpose of this thesis is to explore the clinical and biological relationship between depressive symptoms and executive dysfunction following mild traumatic brain injury (mTBI) or concussion in pediatric populations. Chapter 1 provides an overview of the literature surrounding children and youth with concussive injury as it pertains to executive dysfunction and depressive symptoms. Chapter 2 describes the clinical nature of the relationship between depressive symptoms and executive dysfunction. The results demonstrate that individuals with elevated depressive symptoms had comparable performance to individuals with normal levels of depressive symptoms on executive function scores. This included their performance on an inhibitory control task in which emotional distractors were presented. Regardless of levels of depressive symptoms, adolescents with concussive injury displayed impaired executive functioning compared to normative data, which emphasizes the importance of evaluating executive function following concussion. Chapter 3 involves the use of functional brain imaging to explore the physiological differences between adolescents with average and elevated depressive symptoms on emotion-mediated inhibitory control processes. The group as whole did not display activity in the frontostriatal regions that are associated with inhibitory control, which suggests a potential impairment in this network. Adolescents with elevated depressive symptoms displayed fewer areas of activity compared to adolescents with average levels of depressive symptoms. As a number of individuals (particularly those with elevated depressive symptoms) were injured in the occipital region of the skull, the coup-contrecoup impact may have resulted in frontal lobe injury. Faces were used to evoke emotional processing throughout the inhibitory control task. The results revealed that adolescents with elevated depressive symptoms were more likely to engage in brain regions subserving evaluative processing of social interactions. This might suggest that depressive symptoms display differences in physiology when emotional stimuli are present. These findings provide insight into the role the environment plays in contributing to the cognitive demands placed on adolescents recovering from concussion. Chapter 4 reviews the key messages derived from these results and describes their clinical relevance. This exploration may lead to a more holistic understanding of concussion and a better approach to injury management, particularly for adolescents who express higher levels of depressive symptoms following concussion. / Thesis / Master of Science (MSc)