This thesis describes studies assessing the ability of somatosensory evoked potentials (SEPs) to predict outcome following severe brain injury by examining outcome and determining the predictive value of SEPs directly and in comparison to alternative tests in both patients and systematic reviews of the literature. Outcome was assessed using a functional and quality of life measure. It changed over time and was influenced by age, mechanism, timing and the type of outcome measure. When 5 year functional outcome was used, sensitivity and specificity for the initial SEPs were 63.2% and 93.3% with a positive predictive value of 92.3% for favourable outcome and 66.7%, 94.7% and 90.9% for unfavourable outcome prediction. SEPs predictive performance varied and was better in patients with 1 year outcomes, when outcome was measured with the quality of life tool and in patients suffering hypoxicischaemic encephalopathy. Importantly, only twelve false positives were identified in the systematic review of 55 studies from 903 patients with bilaterally absent SEPs. Eight of these false positives suffered focal lesions of the brain stem, large cerebral fluid collections or recent decompressive craniectomy which cause SEPs to be absent because of a mechanical disruption to the electrical signal. Comparisons between SEPs and other tests in the patient cohort and wider literature showed that SEPs were the best overall predictors of outcome but were outperformed by some clinical tests in specific areas. Specificity for unfavourable outcome prediction was better for ICP, CPP and the last pupillary response. In patients with any cause of brain injury, the combination of SEPs and Motor responses provided the best predictions for unfavourable outcome while for favourable outcome the best overall prediction and specificity were achieved with a combination of either SEPs or Motor responses and the best sensitivity with pupillary responses alone or a combination of either SEPs or Pupillary responses. The studies in this thesis provide a detailed evaluation of SEPs and showed that SEPs have a place in the prediction of outcome, alone or in combination with existing tests. Overall, they are superior to clinical tests and can be easily obtained at the bedside and in the presence of pharmacological paralysis and analgesia/sedation.

Traumatic brain injury (TBI) is the leading cause of death and disability in the industrialized world. This pilot study investigated demographic, clinical and environmental factors associated with return to work (RTW) among workers who sustained a mild to moderate work-related TBI (WrTBI). Using a retrospective cohort design, participants were recruited through an outpatient clinic dedicated to evaluating injured workers after a WrTBI. A mailed survey and medical record abstraction tool were used for data collection. Of the 40 injured workers who participated in this study, 19 reported working at time of follow-up. Those who were unable to RTW scored significantly lower on measures of emotional well-being; there were no significant between-group differences in cognitive or physical impairments. Gradual RTW and workplace accommodations were reported as key factors facilitating RTW. Our findings provide information that addresses improved rehabilitation and management of WrTBI as well as better education and support for employers.

Traumatic brain injury (TBI) is the leading cause of death and disability in the industrialized world. This pilot study investigated demographic, clinical and environmental factors associated with return to work (RTW) among workers who sustained a mild to moderate work-related TBI (WrTBI). Using a retrospective cohort design, participants were recruited through an outpatient clinic dedicated to evaluating injured workers after a WrTBI. A mailed survey and medical record abstraction tool were used for data collection. Of the 40 injured workers who participated in this study, 19 reported working at time of follow-up. Those who were unable to RTW scored significantly lower on measures of emotional well-being; there were no significant between-group differences in cognitive or physical impairments. Gradual RTW and workplace accommodations were reported as key factors facilitating RTW. Our findings provide information that addresses improved rehabilitation and management of WrTBI as well as better education and support for employers.

With an estimated incidence of 1.5 million each year, traumatic brain injury (TBI) is a major cause of mortality and morbidity in the United States. Opening of the mitochondrial permeability transition pore (mPTP) is a key event contributing to TBI pathology. Cyclophilin D (CypD), a matrix peptidyl-prolyl cis-trans isomerase, is believed to be the regulating component of the mPTP. Cyclosporin A, an immunosuppressant drug, inhibits CypD and blocks mPTP formation and has been shown to be neuroprotective following TBI. However, it is unclear if CsA’s neuroprotective mechanism is due to inhibition of CypD and/or immuno-suppression. Therefore to directly assess the contribution of CypD to TBI pathology, CypD knockout mice were subjected to a controlled cortical impact model of TBI. CypD ablation resulted in increased tissue sparing, hippocampal protection, and improved mitochondrial complex I driven respiration. Next a dose-response study of the Cyclophilin D inhibitor, NIM811, was performed. NIM811 administration following TBI resulted in improved cognition, increased tissue sparing, and improved mitochondrial function. These results suggest a major role for CypD in TBI pathology and validate CypD as a potential therapeutic target for TBI. TBI has been proposed to be the signature injury of the current Middle Eastern conflicts with an estimated prevalence of 15-60 % among combat soldiers. Although the brain does appear to be vulnerable to blast, the exact mechanisms underlying the injury remain unclear. Adult male Sprague-Dawley rats were exposed to a moderate level of blast overpressure. Following blast, blood brain barrier disruption was evident at 3 and 24 h post-exposure, oxidative damage increased at 3 h post-exposure, and microglia were activated in the hippocampus at 5 and 10 days post-exposure. This may widen future neuroprotective avenues for blast since blast brain injury appears to share similar mechanisms of injury with other TBI models.

Traumatic brain injury (TBI) effects a large number of individuals, both civilians and military personnel, every year. The neuroinflammatory response mounted in the brain following a head injury continues long after the effects of initial subside. While it was initially thought to only occur in moderate or severe TBI, the deleterious effects of this cascade have recently been identified in patients with mild TBI (mTBI). Hypopituitarism is an often underreported condition and can result from TBI of all severity. The long-term sequelae of TBI can manifest in or exacerbate many other comorbidities of brain injury, such as neuroendocrine dysfunction or mental health conditions. Both TBI and hypopituitarism can present with symptoms similar to some psychiatric disorders, or exacerbation comorbid conditions. Veteran patients presenting to their primary care providers with symptoms of irritability, depression, anxiety, or cognitive and behavioral changes may meet criteria to receive diagnoses of psychiatric illnesses prevalent in the military population, while not being evaluated for pituitary dysfunction, and thus receive inadequate treatment. The proposed study aims to identify the prevalence of patients that are receiving psychiatric treatment that have both a history of mTBI and reduced levels of pituitary hormones on serum assays. By identifying a significant portion of this population, future studies can assess the impact that hormonal replacement has on success of psychotherapy, resolution of symptoms, and impact on functional status, among other factors.

This quantitative research is on the efficacy of Minnesota Statute 144.574 enacted in 2005 in response to the growing awareness of behavior leading to inflicted Traumatic Brain Injuries (iTBI) in infants and children. The model for this research is grounded in the Theory of Reasoned Action wherein the education of new parents which graphically explains the physiologic changes to the structural architecture of the brain post-trauma, paired with their signature on a social contract (SC), demonstrated a reduction in incidence. Because the enacted statute does not include the signing of a SC, nor does it require face-to-face education as in the model, Statute 144.574 cannot claim to be completely grounded in medical science. The result is that neither legislators nor the medical and public health community know whether the statute is effective in lowering incidence. This research was designed to explore the difference in the incidence pre-and post-enactment, in rural vs. urban communities, the proportion of incidence and ethnicity, and an ordinal shift in the distribution of severity. All births in Minnesota from 1998 through 2017 were included. Cases defined using International Classification of Disease were extracted from secondary data from the brain and spinal cord injury, hospital discharge, and vital statistics databases. A Z-test was employed to compare the incidence in a control cohort of infants and children born prior to enactment to the incidence of same in an interventional cohort born post-enactment. Results suggest the statute has not resulted in lowering incidence, have uncovered an unanticipated statistically significant increase in rural vs. urban incidence, yet point to a trend in favor of less severe iTBI. These results represent a positive social change which is grounded in the society's imperative and social justice of protecting children by informing public health officials, caregivers, and legislators of the need for meaningful reform and strengthening of programs leading to lowering the incidence of iTBI in children in Minnesota.

Purpose: Interdisciplinary research in epidemiology, neurology, neuroscience, and sports medicine commonly highlight the dangerous short- and long-term sequelae of sport-related concussions (SRC). Despite advancements in clinical evaluation and recognition, many SRCs are not properly diagnosed and managed, leaving many athletes in danger of acute and chronic neurological deficits. Epidemiological studies suggest the prevalence of chronic traumatic encephalopathy (CTE) is three times, and Alzheimer's disease is four times greater in former athletes with a history of SRC than non-athletes. The underlying mechanisms linking SRC and contact-sport participation to neurodegeneration are not fully understood. Herein, I hypothesized that transient insufficiency of the lymphatic and glymphatic clearance systems in the central nervous system (CNS) could play a crucial role in the SRC-mediated neurological conditions. Therefore, this study aimed to examine the differences in plasma levels of extracellular vesicles (EV) that are associated with the lymphatic and glymphatic clearance systems of the CNS among athletes following sport-related head impacts. Participants: Plasma EV concentrations were analyzed in collegiate athletes (controls n=29, SRC n=19) with and without SRC. In a parallel study, fourteen college-aged soccer players participated in a laboratory-based, repetitive subconcussion paradigm. All participants provided written informed consent, and the study was approved by institutional review board at Temple University. Methods: We evaluated EVs containing markers associated with the CNS lymphatic and glymphatic systems, including lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), astrocyte-specific glial fibrillary acidic protein (GFAP), aquaporin 4 (AQP4), and the platelet and endothelial cell adhesion molecule 1(PECAM-1 or CD31). Tetraspanin-28 (CD81) was used as an EV-specific marker. Blood samples from athlete controls were collected once during preseason baseline assessments. Samples from athletes with SRC were collected within 72 hours of injury. Whole blood was double-centrifuged to obtain platelet-poor plasma, snap-frozen in liquid nitrogen, and stored at -80°C until analyzed. Quantification of plasma EVs was performed using spectral flow cytometry. Mann-Whitney U tests were used for group comparisons of single and double-positive EV concentrations, and receiver-operating characteristic curve (ROC) and area under the curve (AUC) analyses assessed diagnostic efficacy. Within-group changes in plasma EVs following repetitive, subconcussive head impacts were assessed with Friedman's test using Dunn's correction for multiple comparisons. Results: Among athletes with SRC, plasma concentrations of LYVE1+EVs and CD31+EVs were significantly elevated within 72 hours of injury compared to controls (LYVE1+EVs, p < 0.0001; CD31+EVs, p = 0.005). ROC analysis revealed plasma concentrations of LYVE1+EVs demonstrated significant diagnostic accuracy to differentiate athletes with SRC from athlete controls (AUC: 0.971, 95% C.I. = 0.933-1.000, p < 0.0001). Notably, concentrations of LYVE1+/CD81+ double-positive EVs, CD31+/CD81+ double-positive EVs, and GFAP+/CD81+ double-positive EVs were significantly higher among athletes with SRC within 72 hours of injury compared to control athletes (p < 0.0001; p = 0.0002; p < 0.0001, respectively). Plasma AQP4+/GFAP+ double-positive EVs and AQP4+/CD81+ double-positive EVs were not. However, plasma concentrations of GFAP+/CD81+ double-positive EVs and AQP4+/GFAP+ double-positive EVs were significantly elevated after repetitive, subconcussive head impacts (p < 0.0001 and p = 0.004, respectively). Conclusion: Plasma concentrations of double-positive EVs, including LYVE1+/CD81+EVs, CD31+/CD81+EVs, and GFAP+/CD81+EVs, may be promising biomarkers for acute SRC. EVs associated with the glymphatic system, GFAP+/CD81+EVs and AQP4+/GFAP+EVs, were significantly elevated after repetitive subconcussive head impacts. The differences observed in EV responses to SRC and subconcussion may provide novel mechanistic insights about sport-associated neurodegeneration for current and future athletes. / Kinesiology

Thesis (MA)-- Stellenbosch University, 2014. / ENGLISH ABSTRACT: Family caregivers play a large role in the lives of traumatic brain injury (TBI) survivors. This study explored the experiences of family members who care for TBI survivors in the Western Cape. Emphasis was placed on the challenges and resources that were associated with the caregiving role. A qualitative exploratory research design was implemented, whereby thematic analysis was utilised to examine the semi-structured interviews that were conducted with 12 female family caregivers of TBI survivors. Several challenges emerged, namely trauma, consequences of a TBI, responsibilities, lack of support, unawareness, financial burden, emotional challenges and coping. Several resources were also identified, namely the road to recovery, social support, financial resource and coping. These findings suggest that although caregivers who care for a family member who sustained a TBI face several challenges through the caregiving task, these individuals have a number of resources that help them to cope. Interventions that focus on psycho-education have been identified as an important need amongst the participants of this study. In addition, the need for support groups were highlighted as an important way in which many of the challenges that these caregivers experience could be addressed. Caregivers also expressed a need for more active involvement of health care professionals with regard to the provision of guidance, empathy and information. It seems as if the caregivers view the relationship between themselves and the health care professionals involved in the treatment of their family member who sustained a TBI as very important. It was however evident from the findings of this study that the caregivers are generally not satisfied with the quality of the interaction between the health care professionals and themselves. This study’s findings serve as a basis for future research studies on the experiences of family caregivers of TBI survivors in the Western Cape. / AFRIKAANSE OPSOMMING: Gesinsversorgers speel ’n groot rol in die lewens van oorlewendes van traumatiese breinbeserings (TBB). Hierdie studie het die ervaringe van gesinsversorgers van TBB-oorlewendes in die Wes-Kaap verken. Die fokus is op die uitdagings en hulpbronne wat geassosieer word met die versorgingsrol. ’n Kwalitatiewe ontwerp is geïmplementeer, waarby tematiese analise gebruik is om die semigestruktureerde onderhoude van 12 vroulike gesinsversorgers van TBB-oorlewendes te bestudeer. Verskeie uitdagings het na vore gekom, naamlik trauma, gevolge van TBB, verantwoordelikhede, gebrek aan ondersteuning, onbewustheid, finansiële las, emosionele uitdagings en hantering. Die hulpbronne wat geïdentifiseer is, het die pad na herstel, sosiale ondersteuning, finansiële hulpbron en hantering ingesluit. Intervensies wat fokus op psigo-opvoeding is geïndentifiseer as ’n belangrike behoefte onder die deelnemers aan die studie. Hierbenewens is ook ’n behoefte aan ondersteuningsgroepe uitgelig as ’n belangrike wyse om die vele uitdagings wat hierdie versorgers ervaar aan te pak. Die versorgers het ook ’n behoefte ervaar aan meer aktiewe betrokkenheid van gesondheidskundiges ten opsigte van die voorsiening van leiding, empatie en inligting. Dit blyk dat versorgers die verhouding tussen hulself en die gesondheidskundiges betrokke by hul gesinslid met die TBB as belangrik beskou. Desnietemin blyk dit duidelik uit die bevindinge van hierdie studie dat versorgers oor die algemeen nie tevrede is met die kwaliteit van die interaksie tussen die gesondheidskundiges en hulself nie. Die bevindinge van hierdie studie dien as basis vir toekomstige navorsing oor die ervaringe van gesinsversorgers van TBB-oorlewendes in the Wes-Kaap.

ABSTRACT: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery. METHODS: Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9-10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry. RESULTS: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores. CONCLUSION: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI.

Objectives: There is evidence that childhood traumatic brain injury (TBI) is associated with increased risk of offending and violent crime. This study aimed to explore associations between TBI in a group of delinquent and vulnerable young people (VYP) at risk of offending, and facial emotion recognition (FER) abilities, inhibition control (Stop-IT) and self-reported reactive-proactive aggression (RPQ). Methods: There were two studies. The first study used a cross sectional between group design to compare 45 VYP (with and without TBI) and a control group of 59 students on FER task measuring emotion recognition accuracy of six basic emotions. The second study examined differences between TBI and non-TBI groups in the VYP sample (N=21) on a Stop-IT task, FER accuracy and self-reported reactive-proactive aggression. Results: A history of TBI was reported by 60% of the VYP group (48.9% with loss of consciousness [LoC]), whereas 30% of the control group reported a history of TBI (25.4% with LoC). The VYP group (with and without TBI) demonstrated a similar pattern of reduced overall FER accuracy that was significantly different to the control group. Compared to the control group, The VYP groups (with and without TBI) were less accurate on recognising anger, disgust, sadness and surprise, but not happy and fear. There were no significant differences between the TBI- and non-TBI groups. The second study did not find any significant differences between the TBI and non-TBI groups on overall FER accuracy, Stop-IT performance, and RPQ scores. There were also no significant associations between these measures. Conclusions: Future research requires larger samples that enable investigating the association between different severity of TBI, FER and inhibition control ability. Better and more youth-friendly measures are also needed.