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.

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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

Background: Previously, we had shown that elevation of cerebral perfusion pressure, using pressors, improved short-term outcomes after traumatic brain injury and hemorrhagic shock in swine. The current study evaluates outcomes after resuscitation with diaspirin cross-linked hemoglobin (DCLHb)-a hemoglobin-based oxygen carrier with pressor activity-in the same swine model of traumatic brain injury and hemorrhagic shock. Methods: Anesthetized and ventilated swine received traumatic brain injury via cortical fluid percussion (6-8 atm) followed by 45% blood volume hemorrhage. One hour later, animals were randomized to either a control group (SAL) resuscitated with normal saline equal to three times shed blood volume or to one of two experimental groups resuscitated with DCLHb. The two experimental groups consisted of a low-dose group, resuscitated with 250 mL of DCLHb (Hb1), and a high-dose group, resuscitated with 500 mL of DCLHb (Hb2). Animals were observed for 210 minutes postresuscitation. Outcomes evaluated were cerebral oxygenation by measuring partial pressure and saturation of oxygen in cerebrovenous blood; cerebral function by evaluating the preservation and magnitude of cerebrovascular carbon dioxide reactivity; and brain structural damage by semiquantitatively assessing beta amyloid precursor protein positive axons. Results: Postresuscitation, cerebral perfusion pressure was higher in the DCLHb groups (p < 0.05, Hb1 and Hb2 vs. SAL), and intracranial pressure was lower in the Hb2 group (p < 0.05 vs. SAL). Cerebrovenous oxygen level was similar in all groups (p > 0.05). At baseline, 5% carbon dioxide evoked a 16 ± 1% increase in cerebrovenous oxygen saturation, indicating vasodilatation. At 210 minutes, this response was nearly absent in SAL (4 ± 4%) (p < 0.05 vs. baseline) and Hb1 (1 ± 5%), but was partially preserved in Hb2 (9 ± 5%). There was no intergroup difference in beta amyloid precursor protein positive axons. Five of 20 SAL and 0 of 13 DCLHb animals developed brain death (flat electroencephalogram) (p = 0.05, SAL vs. DCLhb). Postresuscitation, DCLHb animals maintained higher mean pulmonary arterial pressure (28 ± 1 mm Hg, SAL; 42 ± mm Hg, Hb1; 45 ± 1 mm Hg, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL) and lower cardiac output (3.9 ± 1.6 L/min, SAL; 2.6 ± 0.1 L/min, Hb1; 2.7 ± 0.1 L/min, Hb2) (p < 0.05, Hb1 and Hb2 vs. SAL). Three Hb2 animals died as a result of cardiac failure, and one SAL animal died as a result of irreversible shock. Conclusion: In this swine model of traumatic brain injury and hemorrhagic shock, resuscitation with DCLHb maintained a higher cerebral perfusion pressure. Low-dose DCLHb (minimal increase in oxygen carriage) failed to significantly improve short-term outcome. With high-dose DCLHb (significant improvement in oxygen carriage), intracranial pressure was lower and cerebrovascular carbon dioxide reactivity was partially preserved; however, this was at the cost of poorer cardiac performance secondary to high afterload.

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