One of the serious public health problems is the Traumatic Brain Injury, also known as silent epidemic, affecting millions every year. Management of these patients essentially involves neuroimaging and noncontrast CT scans are the first choice amongst doctors. Significant anatomical changes identified on the neuroimages and volumetric assessment of haemorrhages and haematomas are of critical importance for assessing the patients’ condition for targeted therapeutic and/or surgical interventions. Manual demarcation and annotation by experts is still considered gold standard, however, the interpretation of neuroimages is fraught with inter-observer variability and is considered ’Achilles heel’ amongst radiologists. Errors and variability can be attributed to factors such as poor perception, inaccurate deduction, incomplete knowledge or the quality of the image and only a third of doctors confidently report the findings. The applicability of computer aided dianosis in segmenting the apposite regions and giving ’second opinion’ has been positively appraised to assist the radiologists, however, results of the approaches vary due to parameters of algorithms and manual intervention required from doctors and this presents a gap for automated segmentation and estimation of measurements of noncontrast brain CT scans. The Pattern Driven, Content Aware Active Contours (PDCAAC) Framework developed in this thesis provides robust and efficient segmentation of significant anatomical landmarks, estimations of their sizes and correlation to CT rating to assist the radiologists in establishing the diagnosis and prognosis more confidently. The integration of clinical profile of the patient into image segmentation algorithms has significantly improved their performance by highlighting characteristics of the region of interest. The modified active contour method in the PDCAAC framework achieves Jaccard Similarity Index (JI) of 0.87, which is a significant improvement over the existing methods of active contours achieving JI of 0.807 with Simple Linear Iterative Clustering and Distance Regularized Level Set Evolution. The Intraclass Correlation Coefficient of intracranial measurements is >0.97 compared with radiologists. Automatic seeding of the initial seed curve within the region of interest is incorporated into the method which is a novel approach and alleviates limitation of existing methods. The proposed PDCAAC framework can be construed as a contribution towards research to formulate correlations between image features and clinical variables encompassing normal development, ageing, pathological and traumatic cases propitious to improve management of such patients. Establishing prognosis usually entails survival but the focus can also be extended to functional outcomes, residual disability and quality of life issues.

Magister Scientiae (Occupational Therapy) - MSc(OT) / An estimate of 89 000 cases of new traumatic brain injuries (TBI) are reported annually in South Africa. South African legislation advocates for the employment of persons with a disability. Individuals with mild-moderate TBI that do qualify to return-to-work (RTW) often do not have access to vocational rehabilitation (VR) and, as a result, return to the occupational therapy work assessment units for Disability Grant assessments. Not having the necessary insight and understanding about the condition influences the affected individual’s chances of returning to work. Failing to return to work results in dependency on a caregiver. The aim of this study was to explore the perceptions and experiences of employers and caregivers of individuals with mild traumatic brain injury returning to work after completing a VR programme, using the Model of Occupational Self-Efficacy. A purposive sample comprising employers and caregivers of 10 individuals with mild TBI was selected. Semi-structured interviews were completed and data manually managed, with confidentiality and anonymity strictly ensured. The findings of the study were analysed by means of thematic analysis, from which five themes emerged. Themes one and two described the employers’ and caregivers’ experiences and perceptions that hindered the RTW process. Theme three related to the enabling aspects they derived from engaging in the VR process, along with the individual with mild-moderate TBI. Themes four and five presented the coping strategies that aided the employer and caregiver in playing a continued role in the RTW process. The International Classification of Function, Disability and Health (ICF) was used to conceptualise the findings and interpret the perspective of the barriers, enablers and coping strategies as seen through the lens of the employer and caregiver. The results of the study can be used to help individuals with TBI adapt to the work environment, as well as inform policy development regarding social grants and access to rehabilitation services for TBI survivors. Occupational therapists (OT) using the MoOSE should regard the employer and caregiver as key role players during therapy. Employers should gain a better understanding of TBI and allow for sick leave during rehabilitation. Caregivers would benefit from finding or establishing a support network for themselves, and by connecting with employers of the individual with TBI in order to understand the individual’s work environment.

Traumatic brain injuries (TBI) are one of the leading causes of disability worldwide (Zitnay, 2008), yet one of the least understood neurological conditions (Duncan, 2005). Research has examined short-term deficits; however, less focus has been on the consequences of multiple concussions. Previous electroencephalography (EEG) concussion research has examined the N200 and P300 human event-related potential (ERP) components, yielding inconclusive results (Duncan, Kosmidis & Mirsky, 2005). An ERP component not as frequently examined is the reward positivity, generated by the anterior cingulate cortex (ACC), a region which experiences increased anatomical stress following injury. In this study, 51 students from the University of Victoria took a ‘Concussion Survey’ to determine participant history and groups; no history of concussion, a single injury or multiple injuries (2+). Participants performed an oddball and decision-making task while EEG data was collected. No significant differences were found between groups for the N200, P300 or reward positivity peak latencies or amplitudes. Both concussion groups yielded attenuated peak amplitudes, but no differences existed between the group with a single concussion versus multiple. Unexpectedly, N200 and reward positivity peak latencies were greater in the group with single injuries, compared to those with a history of multiple concussions. This study adds to a continuous line of inconclusive research on the N200 and P300, suggesting minimal cognitive deficits result from concussive injuries. Furthermore, no noticeable differences were observed between groups with a single versus multiple injuries. While the ACC is located in a region of increased stress following TBI, functional deficits impacting the reward positivity may not be as significant as previously hypothesized. Results may be impacted by confounding variables, including not reliably being able to account for time since injury, injury severity and differences in gender dispersion of participants. With concussions on the rise, continued research, particularly longitudinally and within-subjects is critical for the advancement of both TBI prevention and management. / Graduate

Concussions are debilitating injuries affecting the short and long-term health of those who suffer from them. While an increased awareness of the injury has helped lead to a better understanding of the importance of better monitoring and treatment protocols, concussive injuries continue to occur at an alarming rate. Current injury risk thresholds exist and are used in the development of better equipment to protect athletes in high impact sports, however much of this data is based on simulations and/or cadaveric and animal model data from falls. Thus, there is a lack of data from concussive injuries resulting from a multitude of injury events within different sports, including collisions, falls and punches. The purpose of this thesis was to use dynamic response characteristics and brain tissue response to compare four different injury events from reconstructions of real life concussive injury events. This research was designed to provide information related to brain trauma characteristics specific to four common concussive brain injury events. Seventy-two (72) injury reconstructions were used in this study involving four injury events; collisions, helmeted falls, unhelmeted falls and punches. The results from the first study revealed that while all injury events produced similar MPS and Von Mises stress values, the injury events produced different peak linear and rotational accelerations. In terms of risk for concussive injury, differences were also found between percent risk for concussion and the specific injury events, questioning the validity of current concussive thresholds’ applicability to across all types of concussive injury events. The second study aimed to characterize each concussive injury event by means of specific kinematic characteristics unique to that particular event. The results showed that dynamic response variables that accounted for the most variance changed dependant on the concussive producing event. The third study compared maximal principle strain and strain fields within the brain by the specific injury event. The results showed that global strain within specific regions of the brain were significantly different between the different injury events. Furthermore, unique strain fields within the cerebrum were found between the four concussive injury events. The three studies in this research program characterize four common concussive injury events found in sport. It aimed to describe the unique dynamic response characteristics for each injury event that may have significant influence on protective equipment development and standards testing. Finally, though the aim of this study was not to correlate location of strains within the brain with onset of concussive symptoms and duration, this study demonstrated that the concussive producing event can have an effect on location of peak strain and strain field within regions of the cerebrum associated with concussive symptoms.

Brain injury, either surgically induced or as a result of trauma or stroke, is one of the leading causes of death and disability worldwide. Since transplantable stem cell sources are showing a great deal of promise and are actively being pursued to provide neuroprotection post-injury, in this body of work, we set out to characterize and examine the therapeutic potential of amniotic fluid derived (AF) cells as a potential cell source for cell-based therapies in mediating neuroprotection post-injury. Despite their heterogeneity, we found that AF cells are mainly epithelial in origin and express various genes involved in stem cell maintenance and neural commitment. A very small subset of AF cells also express pluripotency markers OCT4a, SOX2 and NANOG, which can be enriched for by single cell cloning. SOX2 positive clones have the capacity to give rise to a neuronal phenotype, in neural induction conditions, which can be used to examine the neural differentiation capabilities of AF cells. Subsequently, we examined the ability of AF cells to mediate a neuroprotective effect in a surgically induced brain injury model through gap junctional-mediated direct cell-cell communication and as a vehicle for GDNF delivery post-injury. AF cells express high levels of CX43 and are able to establish functional gap junctional intercellular communication (GJIC) with cortical astrocytes. We report an induction of Cx43 expression in astrocytes following injury and demonstrate, for the first time, CX43 expression at the interface between implanted AF cells and host astrocytes. In an effort to boost host endogenous neuroprotective mechanisms post-injury, via neurotrophic factor delivery, we engineered AF cells to secrete GDNF (AF-GDNF). GDNF pre-treatment significantly increased AF cell and cortical neuron survival rates following exposure to hydrogen peroxide. AF-GDNF cells, seeded on polyglycolic acid (PGA) scaffolds, survived longer in serum-free conditions and continued to secrete GDNF post-implantation activating the MAPK/ERK signaling pathway in host neural cells in the peri-lesion area. Despite some promising trends, we did not observe significant behavioural improvements following AF-GDNF/PGA implantation nor reduced lesion volume during the 7 day time-frame. In conclusion, through GJIC with cortical astrocytes and delivery of exogenous neurotrophic factors, AF cells hold great promise in mediating neuroprotection post-injury.

This study examined the effectiveness of cautioning and education on simulating a mild traumatic brain injury on several neuropsychological measures. The measures used included the Word Memory Test (WMT), Wechsler Adult Intelligence Scales® - Third Edition (WAIS®-III), Wechsler Memory Scales®-3rd Edition instrument (WMS®-III), 16-item version of the Rey Memory Test, and a self-report symptom checklist. Five experimental groups were used including clinical and non-clinical controls, as well as three simulation groups. The design and implementation of this study also attempted to correct several methodological short comings of prior research by increasing the incentives for participants, expanding the generalizability of findings and examining research compliance and participant self-perception through debriefing. Discriminant analysis was utilized to determine if specific functions existed that would correctly classify and distinguish each experimental group. Several discriminant functions had at least moderate canonical correlations and good classification accuracy. Results also include utility estimates given projected varying base rates of malingering.

Le traumatisme cranio-cérébral (TCC) est l'une des plus grandes causes de mortalité et de morbidité de ce siècle. Les études menées ces dernières années sur ce sujet, ont montré que l'hypopituitarisme est une des conséquences les plus fréquentes et les plus durables consécutives à un TCC. L'hypopituitarisme se traduit par une ou des déficience(s) hormonale(s) et notamment une diminution de la sécrétion de l'hormone de croissance (GH). Mes travaux de thèse ont consisté à mettre en place un model murin pour étudier le déficit en GH après un TCC ; et ainsi rechercher à quel niveau l'axe somatotrope est-il touché. J'ai tout d'abord participé à des études qui m'ont permis de mettre en place des pré-requis expérimentaux à l'étude du TCC sur des souris (J. Endoc. 2009 ; PNAS, 2010). Dans ce modèle animal, 10% à 20% de ces souris traumatisées présentent un défaut de sécrétion de la GH trente jours après avoir subi un TCC au niveau du cortex pariétal droit, ont un défaut de sécrétion de la GH, alors que les animaux opérés mais non traumatisés (sham) ne présentent pas ce défaut. Les souris déficientes pour la sécrétion de GH ne présentent pas de dérégulation de l'architecture vasculaire hypophysaire ou hypothalamique. Au niveau moléculaire, la transcription des ARNm de l'hormone de croissance et de la neurohormone hypothalamique GHRH (qui stimule la sécrétion de GH) ne semble pas affectée par les effets du traumatisme. En revanche, très rapidement après un traumatisme localisé au niveau du cortex, on observe l'apparition d'une cicatrice gliale. Cette cicatrice astrocytaire apparait non seulement dans la région du traumatisme, mais également au niveau de l'éminence médiane. Cette réponse inflammatoire, associée à un défaut des tanycytes bordant le 3ème ventricule, pourrait expliquer, au moins en partie, ce déficit en GH post-TCC. En résumé, cette étude nous a permis de reproduire sur le modèle murin (avec un même fond génétique) les déficits en GH que l'on observe chez des patients traumatisés. / Traumatic Brain Injury (TBI) is a major cause of mortality and morbidity. Studies on this subject in recent years have revealed that hypopituitarism is one of the most common sequelae to TBI. Since the pituitary is an endocrine tissue, hypopituitarism results in marked hormonal deficiency, including decreased serum levels of growth hormone. As such, the work contained within this thesis has focused on developing a mouse model of TBI-induced GH deficiency, with the principal aim of discovering where the deficit lies in the somatotropic axis (i.e. hypothalamaic releasing hormone vs. pituitary cell activity). By subjecting mice to a controlled impact to the right parietal cortex, we observed a GH secretory defect in 10% to 20% of cases. These defects where apparent thirty days following trauma and were not detected in animals subjected to surgery, but not TBI (sham). Mice suffering hypopituitarism secondary to TBI did not show any obvious changes to pituitary or hypothalamic vascular architecture, and at the molecular level, GH and GHRH (the major GH-secretagogue) mRNA levels were normal. However, in the acute phase following TBI, a large glial scar developed which extended to the level of the median eminence (ME). This inflammatory response could explain, at least in part, GH deficiency post-TBI if associated with dysfunction of third ventricle tanycytes known to be involved in hypothalamic neuron output. In summary, by using an isogenic, age-matched mouse model of TBI, this study has provided insights into the causes of GH deficiency, a common consequence of cranial trauma in humans.

abstract: Traumatic brain injury (TBI) affects an estimated 1.7 million people in the United States each year and is a leading cause of death and disability for children and young adults in industrialized countries. Unfortunately, the molecular and cellular mechanisms of injury progression have yet to be fully elucidated. Consequently, this complexity impacts the development of accurate diagnosis and treatment options. Biomarkers, objective signatures of injury, can inform and facilitate development of sensitive and specific theranostic devices. Discovery techniques that take advantage of mining the temporal complexity of TBI are critical for the identification of high specificity biomarkers. Domain antibody fragment (dAb) phage display, a powerful screening technique to uncover protein-protein interactions, has been applied to biomarker discovery in various cancers and more recently, neurological conditions such as Alzheimer’s Disease and stroke. The small size of dAbs (12-15 kDa) and ability to screen against brain vasculature make them ideal for interacting with the neural milieu in vivo. Despite these characteristics, implementation of dAb phage display to elucidate temporal mechanisms of TBI has yet to reach its full potential. My dissertation employs a unique target identification pipeline that entails in vivo dAb phage display and next generation sequencing (NGS) analysis to screen for temporal biomarkers of TBI. Using a mouse model of controlled cortical impact (CCI) injury, targeting motifs were designed based on the heavy complementarity determining region (HCDR3) structure of dAbs with preferential binding to acute (1 day) and subacute (7 days) post-injury timepoints. Bioreactivity for these two constructs was validated via immunohistochemistry. Further, immunoprecipitation-mass spectrometry analysis identified temporally distinct candidate biological targets in brain tissue lysate. The pipeline of phage display followed by NGS analysis demonstrated a unique approach to discover motifs that are sensitive to the heterogeneous and diverse pathology caused by neural injury. This strategy successfully achieves 1) target motif identification for TBI at distinct timepoints and 2) characterization of their spatiotemporal specificity. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2020

Sports-related concussions are one of the most complex injuries in the sports medicine field since head traumas are hard to recognize, discover and manage. Adolescent brains are under development and therefore more sensitive to concussions. Even though it is well established that concussions are a frequently occuring injury amongst youths, research on concussions on the youth ice hockey level in Sweden have not been previously investigated. Therefore, the primary aim of the present study was to investigate the cumulative prevalence of concussions amongst ice hockey players 13-15 years of age. A total of 188 players were invited to participate. The response rate was 40% whereas 61 players (girls n=6, boys n= 55) met the inclusion criteria. More than one-third (41%) reported at least one concussion, the majority of them hockey related. The study did not only investigate the prevalence of concussions, the understanding on concussions have also been examined, which revealed that half of the participants recognized Hjärntrappan. Although the study could not detect any significant relationship regarding potential risk factors and reported concussions, the investigation have illuminated a complex injury. In conclusion, the prevalence of concussions in the cohort was relatively high since more than one-third (41%) reported at least one concussion. Further, half of the participants recognized Hjärntrappan. The result emphasizes more education regarding head traumas for players, coaches and parents in youth ice hockey in order to prevent disastrous consequences such as premature career ending, future cognitive dysfunction and mental illness.

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