Stroke increases neurogenesis (birth of new neurons) through upregulation of ciliary neurotrophic factor (CNTF), a potent neurogenic cytokine made almost exclusively in the central nervous system. Previous study found that CNTF is induced and needed to stimulate neurogenesis in the subventricular zone (SVZ) of mouse brain in a stroke model. CNTF also has a neuroprotective function. Focal adhesion kinase (FAK), protein tyrosine kinase 2, is ubiquitously expressed in various cell types and mediates cell adhesion and migration. We previously discovered that systemic inhibition of FAK upregulates CNTF expression in the SVZ, making FAK a pharmacological target to increase CNTF to promote neurogenesis and neuroprotection after stroke. This study examined whether systemic FAK inhibitor treatment after stroke regulates SVZ neurogenesis and neuroprotection using a middle cerebral artery occlusion (MCAO) to induce a stroke in adult male C57BL/6 mice. A filament was inserted in the external carotid artery and then fed through the carotid bifurcation into the internal carotid artery to the base of the middle cerebral artery. After 30 minutes of occlusion, the filament was removed to restore blood flow. Mice were randomly assigned to receive 3 daily doses of saline or FAK inhibitor (FAK14, i.p., 3 mg/kg) and treatment started at 6 hours, 12 days, or 58 days after MCAO. Because CNTF has a neuroprotective function, the amount of tissue damage was analyzed to compare treatment groups. The neuroprotective role of FAK14 was examined by measuring MCAO-induced infarction. The infarct size was measured using the absence of NeuN (neuronal cell marker) and GFAP (activated astrocytes) and presence of CD68 (activated microglia). FAK14 given at 6 hours post-stroke reduced the infarct size to 38% of the uninjured side of the brain compared to 46% with saline. Proliferating cells were labeled by injecting bromodeoxyuridine (BrdU, 50 mg/kg), the mice were processed 2 h after the last BrdU injection, and proliferated cells in the SVZ were counted with unbiased stereology. There were no significant differences in the total numbers of BrdU+ cells between saline and FAK14 at 3, 14 and 60 days. Future studies are needed to confirm the levels of CNTF at the various times of treatment. If there is no difference in CNTF expression or increased expression of counteracting cytokines, no difference in neurogenesis between groups would be expected. The neuroprotective effect of FAK14 during the acute phase following injury could provide novel pharmacological options to stroke patients extending the current therapeutic treatment window.

abstract: Mild TBI (mTBI) has been associated with subtle executive function (EF) and cognitive-communication deficits. In bilinguals, there are unique cognitive demands required to control and process two languages effectively. Surprisingly, little is known about the impact of mTBI on EF, communication, and language control in bilinguals. Therefore, the aim of this study was to examine the cognitive-communication abilities in bilinguals with a history of mTBI, identify any language control impairments, and explore the relationship between these language control impairments and domain-general cognitive control abilities. To this end, three-hundred and twenty-seven monolingual and bilingual college students with and without mTBI history participated in two experiments. In these experiments, EF, communication, and language control were examined using experimental and clinical tasks as well as self-rating scales. In Experiment 1, there was an interaction between mTBI history and language group (monolinguals vs. bilinguals) in how participants performed on a clinical measure of EF and a verbal fluency task. That is, only bilinguals with mTBI scored significantly lower on these tasks. In addition, there was a significant correlation between errors on a language switching task and performance on non-verbal EF tasks. In Experiment 2, a subgroup of bilinguals with persistent cognitive and behavioral symptoms reported greater everyday communication challenges in their first and second languages. Also, unbalanced bilinguals reported greater EF difficulties than monolinguals and balanced bilinguals regardless of mTBI history. In conclusion, bilinguals may face unique cognitive-communication challenges after mTBI. Factors related to the bilingual experience (e.g., language balance, daily language use) should be considered in clinical evaluation and future research. / Dissertation/Thesis / Doctoral Dissertation Speech and Hearing Science 2020

Traumatic brain injury (TBI) is considered the “signature injury” for United States Veterans who deployed in support of Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) since 2001. Veterans with TBI may be at higher risk for subsequent intentional and unintentional injuries due to cognitive and executive function impairments from the injury and co-occurring psychiatric conditions. This dissertation evaluated the association between TBI and attempted suicide, motor vehicle accidents, and opioid overdose, in a large cohort of United States OEF/OIF/OND Veterans aged 18 to 40 who received care in the Veterans Health Administration (VHA). These studies utilized data from the VHA electronic medical records collected between April 2007 and September 2012. Study 1 evaluated the association between TBI and attempted suicide. Veterans with TBI had approximately a 4-fold increased risk of attempted suicide compared to those without, adjusting for demographics (adjusted hazard ratio (aHR): 3.73, 95% CI = 3.07, 4.53). The mediation analyses suggested that the psychiatric conditions substantially attenuated the impact of TBI on attempted suicide (aHR: 1.25 (95% CI = 1.05, 1.48). Study 2 evaluated the association between TBI and motor vehicle accidents. Veterans with TBI had a 56% increased risk of motor vehicle accident compared to those without, adjusting for demographics (aHR: 1.58, 95% CI = 1.27, 1.97). However, the mediation analyses attenuated this association (aHR: 1.17, 95% CI = 0.96, 1.43). Study 3 evaluated the association between TBI and opioid overdose among OEF/OIF/OND Veterans receiving long-term opioid treatment for non-cancer, chronic pain. Veterans with TBI had 2-fold increased risk for opioid overdose compared to those without, adjusting for demographics (aHR: 2.00, 95% CI = 1.26, 3.16). Nevertheless, the mediation analyses suggested that psychiatric conditions attenuated the impact of TBI on opioid overdose (aHR: 1.38, 95% CI = 0.94, 2.01). In conclusion, these studies add to the literature about risk of intentional and unintentional injuries among Veterans with TBI. Additionally, it highlights that Veterans with TBI and at least one co-morbid psychiatric condition are a particularly vulnerable group with the highest risk for injuries.

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L’inflammation est un processus essentiel à prendre en compte dans la pratique clinique. Nous avons montré durant cette thèse que le statut (neuro)inflammatoire précédant la survenue d’une pathologie cérébrale est à prendre en compte nécessairement puisqu’il modifie drastiquement la réponse inflammatoire suite à un deuxième stimulus comme la survenue d’un AVC. Il est d’autant plus important que 90% des AVC sont associés à des comorbidités comme l’hypertension artérielle, le diabète ou la consommation chronique d’alcool, qui ont d’ores et déjà été décrites comme des maladies avec une composante inflammatoire. Nous avons caractérisé ce statut neuroinflammatoire silencieux, aussi appelé priming, dans le cadre de la consommation chronique d’alcool et dans le traumatisme crânien léger. De plus, nous avons identifié les macrophages périvasculaires comme participants à l’effet aggravateur du priming inflammatoire sur les lésions ischémiques. Ils semblent alors être une cible thérapeutique de choix et feront l’objet de futures études. Il est donc nécessaire de trouver des techniques d’imagerie non invasives pour détecter le priming. L’autoradiographie ciblant le TSPO nous a permis de révéler le priming inflammatoire dans le cadre du traumatisme crânien léger. Nous proposons, au vu de nos résultats obtenus durant cette thèse, la tomographie par émission de positons pour la détection de la neuroinflammation invisible dans les atteintes cérébrales aigüe(s) et chronique(s). / Inflammation is an essential process to be considered in clinical practice. We have shown during this thesis that the (neuro)inflammatory status preceding the occurrence of a cerebral pathology must necessarily be taken into account since it drastically modifies the inflammatory response following a second stimulus such as stroke. This is even more important given that 90% of strokes are associated with comorbidities such as chronic hypertension, diabetes or chronic alcohol consumption, for which inflammation is an important pathophysiological feature. We have characterized this silent inflammatory status, also called priming, in the context of chronic alcohol consumption and in mild traumatic brain injury. We have identified perivascular macrophages (PVM) as mediators of the aggravating effect of inflammatory priming on ischemic stroke. PVM appear to be potential therapeutic targets and will be the subject of future investigations. It is therefore necessary to find non-invasive imaging techniques to detect inflammatory priming. We show that autoradiography targeting TSPO reveals the inflammatory priming provoked by a single mild traumatic brain injury. We propose, in light of the results obtained during this thesis, the positron emission tomography imaging to detect the invisible neuroinflammation in acute and chronic brain diseases.

Introduction: Previous research describes significant associations between criminal offending behaviour and traumatic brain injury (TBI). In young offenders, particularly, TBI is significantly more prevalent than in the general youth population. This association might be explained by the fact that key TBI sequelae (e.g., aggression, behavioural and cognitive impulsivity, emotional dysregulation) can place individuals at risk for criminal offending. However, at least two critical questions remain relatively under-investigated: Is there crossnational variability in the prevalence of TBI in young offenders and in the emotional, behavioural, and cognitive profile of young offenders with and without TBI? Few studies report on prevalence of TBI in young offender populations from low- or middle-income countries (LMICs), and fewer describe the neuropsychological profiles of TBI-afflicted young offenders from LMICs. Method: Participants were a South African sample of 25 young offenders and 56 non-offender controls. Conducting such investigations in South Africa is valuable because (a) crime rates, particularly those related to violent offences, are higher in this country than elsewhere in the world, and (b) the prevalence of TBI in South Africa is three times the global rate. All participants were administered self-report measures of emotion regulation, aggression, antisocial behaviour, as well as standardized tests of various executive functions (planning, cognitive flexibility, generative fluency, inhibition, problem solving, and rule learning/maintenance) from the Delis-Kaplan Executive Function System (D-KEFS) battery. I also gathered self-report information about their history of TBI, including whether it was accompanied by loss of consciousness (LoC). Results: Prevalence of TBI was higher in offenders (n = 18/25; 72%) than in non-offenders (n = 24/56; 43%). Offenders reported experiencing more severe TBI: The distribution of TBI with LoC was significantly different across offender and non-offender groups, p < .001. Analyses detected significant main effects of offender status on all outcomes; significant main effects of TBI on emotion regulation, aggression, and antisocial behaviour; and significant offender x TBI interaction effects on emotion regulation and aggression, ps < .036. Conclusion: These findings are broadly consistent with previous studies in this literature. Hence, the present study confirms the importance of understanding associations between TBI and offending (particularly in LMICs) and how the co-occurrence of the two is predictable and can have cumulative effects on affect, behaviour, and cognition. Because sustaining a TBI is preventable, describing the risk for negative outcomes and the socioeconomic costs thereof can inform policy development, rehabilitation planning, and initiatives to reduce recidivism rates.

Traumatic brain injury (TBI) and its associated neural and cognitive sequelae are of increasing interest in military populations. Blast-related TBI is becoming more commonplace in military Service Members and Veterans since Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn and their following conflicts. It is currently unclear whether blast-related injuries cause unique neural and cognitive deficits. The present investigation, in Study 1, aims to investigate the differences in blast-related and non-blast related TBI using traditional statistical techniques. In Study 2, this study will demonstrate the use of Qualitative Comparative Analysis (QCA) in diffusion tensor imaging data. QCA is a relatively new technique that examines configurations of variables that lead to a predefined outcome. QCA has the ability to uncover configurations of variables not yet considered in empirical literature, which may contribute new perspectives on the many different variables often associated with brain injury. Study 1 demonstrated no significant differences between uninjured and injured subjects in white matter integrity, and no differences between blast-related and non-blast related mechanisms. Study 2 demonstrated limited support for the use of QCA in diffusion tensor imaging. Evidence for the use of this method in other neuroimaging modalities is reviewed

Magister Artium (Social Work) - MA(SW) / Recovery from traumatic brain injury (TBI) can be a lengthy and challenging process for survivors, their families, and health and welfare services. Globally, South Africa has the second-highest prevalence of TBI that is due to road traffic accidents. The growing challenges for TBI survivors are the financial constraints, health implications, and the psychosocial support required by survivors of TBI and their families, which impacts family reintegration, post-hospitalisation. The aim of the study was to understand the challenges experienced by TBI survivors with regards to the psychosocial support services for family reintegration. A qualitative approach, using an exploratory-descriptive design was used. The person-centred perspective was chosen as a theoretical framework.