AN ABSTRACT OF THE THESIS OF AIDAN CHRISTIE SMITH, for the MASTER OF ARTS degree in PSYCHOLOGY, presented on OCTOBER 27th, 2017, at Southern Illinois University Carbondale. TITLE: EFFECTS OF NICOTINAMIDE ON MICROGLIAL RESPONSE IN JUVENILE RATS AFTER CONTROLLED CORTICAL IMPACT MAJOR PROFESSOR: Dr. Michael J. Hylin Traumatic brain injury (TBI) is a leading cause of death, cognitive and behavioral disability in children in industrialized nations. Preclinical trials of nicotinamide (NAM) treatment provide neuroprotection and reduced inflammatory responses in adult models of TBI. The primary goal of this study was to address the neuroprotective effects of NAM in the developing brain, specifically, the microglial response that occurs following injury. Animals received a bilateral craniotomy with a single cortical contusion injury over the parietal lobe and were treated with either 500mg/kg of nicotinamide or 0.9% saline via intraperitoneal injection. Animals received three injections, 15 minutes, 24 hours, and 48 hours after injury, and were sacrificed at 4 time points, 3 hours, 72 hours, 1 week, or 1 month following injury. Brains were then used for histological assessment for microglial activity. The results show that NAM attenuates the activation of microglia after CCI. Over the course of time, saline treated animals had a marked increase in microglia at 72 hours and remained elevated after 1 week. In NAM treated animals however, there was no significant increase in the number of microglia at any time point. It is suggested here that NAM has a great effect on the inflammatory response. Further studies are needed to examine NAM’s effects on behavior and functional recovery.

abstract: Approximately 2.8 million Americans seek medical care for traumatic brain injury (TBI) each year. Of this population, the majority are sufferers of diffuse TBI, or concussion. It is unknown how many more individuals decline to seek medical care following mild TBI. This likely sizeable population of un- or self-treated individuals combined with a lack of definitive biomarkers or objective post-injury diagnostics creates a unique need for practical therapies among diffuse TBI sufferers. Practical therapies stand to decrease the burden of TBI among those who would otherwise not seek treatment or do not meet clinical diagnostic criteria upon examination. For this unique treatment niche, practical therapies for TBI are defined as having one or more of the following qualities: common availability, easy administration, excellent safety profile, and cost-effectiveness. This dissertation identifies and critically examines the efficacy of four classes of practical treatments in improving rodent outcome from experimental diffuse traumatic brain injury. Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2017

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

Class of 2013 Abstract / Specific Aims: Guidelines developed by the Brain Trauma Foundation recommend the use of prophylactic anticonvulsants, particularly phenytoin, for the prevention of early posttraumatic seizures for patients with severe traumatic brain injuries. The purpose of this study is to evaluate the effectiveness of levetiracetam, a newer anticonvulsant, for posttraumatic seizure prevention in patients with severe traumatic brain injury. Methods: This study was approved by the University of Arizona Medical Center Institutional Review Board. The project consists of a retrospective cohort analysis from January 1, 2010 to September 30, 2011. We have abstracted data from all patients with traumatic brain injuries over this time period from the University of Arizona Medical Center Trauma Registry, and have matched these patients with their records in the pharmacy database to determine who received levetiracetam versus no prophylaxis. Patients younger than 18 years of age, pregnant women, patients who were deemed to be nonsalvageable, and patients who had a seizure prior to initiation of levetiracetam were excluded from the study. The following data was collected: age, gender, ethnicity, mechanism of injury, injury severity score, ED GCS, ED SBP, ED pulse, ED RR, blood alcohol level, ICU length of stay, number of ventilator days, hospital length of stay, FIM score at discharge (totals, and by component), diagnosis, surgery and complication type, anticonvulsant given, type of beta-blocker given, maximum and minimum dose used, cumulative doses given, and whether there exists a known prior history of anticonvulsant use. All data were recorded without patient identifiers and have been kept confidential. A multivariate logistic regression analysis was used to evaluate a relationship between other data collected from the patients’ medical records and seizure occurrence. Chi Square or Fisher's Exact test will be used in the final analysis to compare the effectiveness of levetiracetam versus no prophylaxis to prevent posttraumatic brain injury seizures. Significance is defined as p<0.05 for all analyses. Main Results: The results are pending the final data analysis. Conclusion: To be determined.

Magister Artium - MA / Traumatic brain injury (TBI) has enjoyed extensive research and several therapeutic modalities, approaches and models have been developed where the main outcomes are focused on the successful return to work of individuals with brain injury. Research into women with TBI has, however, been negligible compared to research into the young adult male population. Gaining insight into how women with traumatic brain injury participate in their work environment would contribute valuable feedback to clinicians utilising return to work approaches and models. The study aimed to explore the challenges women who sustained TBI experience in the work environment after vocational rehabilitation. A qualitative research design was used to explore these experiences and perceptions from ten female participants. The method of data collection used to access the experiences and perceptions of the participants was in-depth semi-structured interviews. Furthermore semi-structured interviews were conducted with two occupational therapist, who were selected as key informants. The data from the study was analysed using thematic analysis. The study further aimed to obtain the participants` perceptions and experiences of barriers and facilitators as well as adaptation processes that influenced their ability to resume their work roles. Four themes originated from the findings of this study. Theme one describes the barriers experienced by women with TBI while returning to work in the form of barriers to work participation for women with TBI, loss of functional capacity hindering return to work, experiences of negative stigma and exploitation in the workplace, and contextual hindrances in the form of parental roles as well as public transportation systems. Theme two describes the factors that facilitated the resumption of the work role for women with TBI. Reestablishing a worker identity by means of vocational rehabilitation, utilising the Model of Occupational Self-Efficacy (MOOSE) as an approach, enabled the women with TBI to overcome their barriers and return to work. Theme three describes an inherent adaptation process where participants could come to terms with their losses, accept the present self and aspire towards a future self, by utilising personalised response approaches to overcome demands and challenges in the work context as well as experiencing success at work by adapting to the work environment. Theme four describes the participants’ views of changes needed in the rehabilitation program and services as well as policies that would aid in the quick return of women with TBI to productive roles. These suggestions are discussed as attainable through developing a multi-dimensional rehabilitation program for women with TBI as well as partnering with relevant stakeholders in the promotion of work opportunities for women with disabilities. The Model of Occupational Adaptation (MOA) was used as a framework to interpret the findings of this study; the barriers, facilitators and adaptation process were assessed as they impact on the experiences of the women with TBIs return to work. The return to work of the women with TBI was not observed only to be influenced by the personal characteristics but also by the environmental context within which the return to work process took place.

Abstract Traumatic Brain Injury (TBI) is a global epidemic (Schwarzbold et al., 2008). According to Brey (2006), a brain injury occurs every 21 second in the United States, which results in 1.5 million head injuries annually. The purpose of this project was to educate psychiatric personnel regarding the needs of the TBI population and to measure learning and retention. This is a quality improvement project that utilized a pretest and posttest design with an educational intervention. The intervention was administered electronically via Microsoft PowerPoint. Results were measured with the Wilcoxon Signed Rank Test. A total of 17 participants completed the pretest and posttest, and 11 completed the second posttest; the second posttest administered six weeks after the initial posttest. The results show that knowledge increased from pretest to posttest, (p < 0.05), however, retention of the material did not occur per test results, (p ≥ 0.05). There is no other research to compare to these results. Therefore, more research and educational intervention are needed to educate psychiatric personnel regarding the needs of the TBI patient.

The identification of sport-related concussion (mild traumatic brain injury [mTBI]), its neurocognitive sequelae, and subsequent management have become a top priority within a spectrum of research disciplines at the intersection of psychology and sports medicine. To properly understand the complex neurocognitive changes associated with sport-related concussion in high school age individuals, multiple aspects of the injury were explored including the psychobiological nature of the injury, diagnostic concerns, normative adolescent neurocognitive development and abnormal changes as a result of the injury, and risk for further injury. While a wealth of literature exists in these areas, one aspect in particular, neurocognitive changes associated with sport-related mTBI in adolescents, is the focus of this research study. A review of the current research reveals a lack of exploration into neurocognitive deficits over-time as early as adolescence. To advance the understanding of how sport-related concussions may influence neurocognitive performance during this vulnerable age for brain development, multiple group comparisons were conducted to determine differences based upon reported concussion history. Results suggest that adolescents who experience sport-related concussion demonstrate significantly reduced levels of neurocognitive performance in several domains on initial baseline testing. Furthermore, these findings generally persist upon follow-up neurocognitive testing during adolescence. Thus, persistent neurocognitive deficits found during adolescence may have profound implications for brain development and concussion management.

The aim of this thesis was to investigate the well-being of patients in clinical neuroscience settings. Both the systematic review and research paper are being prepared for submission to the journal of Neuropsychological Rehabilitation, the guidelines of which are included in the appendices (Appendix 1).Paper one is a systematic review of the literature investigating the prevalence of depression following traumatic brain injury (TBI). 26 papers were reviewed with 15 meeting quality assessment criteria and were described in further detail. The prevalence of depression following TBI, reported in the reviewed studies, varied between 19% and 46%.The quality of the methodology of the studies is evaluated and discussed.The research paper (paper two) investigated the relationship between well-being, cognitive impairment and dependency using care mapping - neurorehabilitation (DCM-NR) as a measure of well-being. This study applied DCM-NR in a range of clinical neuroscience settings. Participants considered to have severe cognitive impairment were found to have significantly lower well-being (as measured by DCM-NR), and to be more dependent than participants with moderate, mild or no cognitive impairment. Overall level of dependency and cognitive impairment accounted for 23.9% of the variance in well-being scores from the DCM-NR.Paper three is a critical appraisal of the systematic review and research paper. Pertinent issues, including methodological limitations, relevant to the two papers are discussed in addition to clinical and research considerations.

Traumatic brain injury (TBI) is one of the leading causes of death and disability in children. The prefrontal cortex (PFC) is most susceptible to injury which leads to deficits in executive function, sociability, and cognitive flexibility. The oxytocin (OT) system plays a significant role in the modulation of species-typical social behaviors, such as social recognition and memory. Intranasal OT (IN-OT) has been shown to be neuroprotective against neuronal insults and social deficits through various mechanisms. Due to this and OT’s role in the modulation of social behaviors, it is possible that IN-OT could improve the social deficits caused by a PFC injury. The primary goal of this study was to determine the effects of a TBI on the development of the OT system. The secondary goal was to address the efficacy of IN-OT as a treatment for the social deficits observed following a TBI. For these studies, animals received a single cortical contusion injury bilaterally damaging the medial pre-frontal cortex. Immediately following injury (1-2 minutes), animals were given a single dose of IN-OT (20 μg, 1 μg/1 μl Ringer’s solution), placebo, or no treatment and sacrificed at days 1, 14, and 30 post-injury. Animals were assessed using behavioral and histological measures. It was predicted that animals that received IN-OT would demonstrate fewer social deficits on the behavioral measures and a smaller lesion size. Additionally, it was expected that a TBI would increase inflammation levels and decrease the levels of OT and OT receptors compared to sham animals. The results indicate that OT treatment did not significantly improve histopathological outcomes. However, the vehicle that was utilized impaired outcomes. Additionally, there was minimal changes to the OT system at the injury site, in the anterior olfactory nucleus, and in the caudate putamen due to injury. But vehicle treatment altered the expression levels of the OT peptide and receptors. Behaviorally, OT treatment improved performance in the Morris water maze in TBI animals compared to vehicle-treated and untreated TBI animals, but not other behaviors. However, vehicle-treated, and OT-treated animals were more likely to be aggressive than expected and untreated sham animals were less likely to be aggressive than expected. Taken together, it was observed that administration of a hypotonic saline solution following TBI significantly increases pathophysiology after TBI, and these effects translate into increased aggression levels. Although, learning and memory remained unaffected by the vehicle. Thus, further studies are needed to examine the effects of OT on TBI for behavioral and pathophysiological improvements.

No description available.