The clinical utility of the Intermediate Category Test, a measure of executive functioning in children 9 to 14 years of age, is currently limited by the availability of only a Total Error score for normative interpretation. The Process Scoring System (PSS) was developed to provide a standardized method of assessing specific processing patterns and problem-solving errors. The purpose of this study was to determine the ability of the PSS scores to discriminate between children with and without suspected executive deficits, thereby providing evidence of criterion-related validity.

Incidents and awareness of sports-related concussion have grown in recent years, attracting attention in both the academic and popular press. These concussions can lead to the rapid onset of neurological dysfunctions, as well as a variety of subjective symptoms. Although concussive sequelae are typically considered transient, debate remains about the persistent effects of repeated traumatic contact during sport participation. Although research has examined the complications of head trauma found in traditionally popular sports (e.g., football, soccer, boxing), little research has focused on the growing sport of mixed-martial-arts (MMA). Research specifically pertaining to MMA is in nascent stages, but to-date studies suggest that concussive injuries for this sport are prevalent and the training regimens of these athletes may place them at a high risk for concussive or subconcussive head traumas—as well as the accompanying neurological difficulties. The current study is the first to assess cognitive profiles of MMA athletes using an objective neuropsychological assessment instrument. Among 56 athletes (28 MMA athletes and 28 athletes not exposed to head traumas), no neuropsychological differences were found between groups of athletes. Additionally, no aspects of MMA training regimen shared a reliable relationship with neuropsychological performance or subjective concussive symptoms. This suggests non-professional participation in MMA may not typically pose a significant risk for cumulative concussions and associated adverse neuropsychological consequences.

Traumatic brain injury (TBI) is the most frequent cause of death in children and young adults in the United States. Besides emergency neurosurgical procedures, there are few medical treatment options to improve recovery in people who have experienced a TBI. Management of patients who survive TBI is complicated by both central nervous system and peripheral systemic effects. The pathophysiology of systemic inflammation and coagulopathy following TBI has been attributed to trauma-induced endothelial cell dysfunction; however, there is little knowledge of the mechanisms by which trauma might impact the functions of the vascular endothelium at sites remote from the injury. The endothelium lining these small vessels normally produces nitric oxide (NO), arachidonic acid metabolites, and endothelial-dependent hyperpolarizing factors to relax the surrounding vascular smooth muscle. For this research study we investigated the effects of fluid-percussion-induced TBI on endothelial-dependent vasodilatory functions in a remote tissue bed (the mesenteric circulation) 24 hours after injury. We hypothesized that TBI causes changes in the mesenteric artery endothelium that result in a loss of endothelial-dependent vasodilation. We found that vasodilations induced by the muscarinic-receptor agonist, acetylcholine, are attenuated following TBI. While the endothelial-derived hyperpolarizing component of vasodilation was preserved, the NO component was severely impaired. Therefore, we tested whether the loss of NO component was due to a decrease in bioavailablity of the NO synthase (NOS) cofactor BH4, the NOS substrate L-arginine, or to changes in expression/activity of the enzyme arginase, which competes with NOS for L-arginine. We found that supplementation of L-arginine and inhibition of the enzyme arginase rescues endothelial-dependent vasodilations in TBI arteries. This study demonstrates that there are pathological systemic effects outside the point of injury following TBI leading to a dysfunctional endothelial vasodilatory pathway. These data provide insight into the pathophysiology of endothelial dysfunction after trauma and may lead to new potential targets for drug therapy.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

La prévalence des troubles du sommeil et de douleur chronique est élevée chez le patient ayant subi un traumatisme crânien cérébral léger (TCCL). L’interaction entre ces plaintes est suggérée chez les patients avec un TCCL mais son étiologie reste encore peu connue. Les résultats de recherche présentés dans le premier article de cette thèse suggèrent que les patients avec un TCCL qui souffrent de douleur ont une modification des ondes cérébrales durant leur sommeil, ce qui pourrait expliquer en partie comment les deux symptômes interagissent. De plus, la douleur, surtout si associée à des troubles de l’humeur, semble jouer un rôle majeur dans la persistance des symptômes post-commotionnels. Le deuxième article de cette thèse décrit une exacerbation des symptômes post-commotionnels chez le patient ayant eu un TCCL et souffrant de douleur. La persistance ou l’apparition de la douleur chronique à long terme serait prédite par le polymorphisme val66met du gène brain-derived neurotrophic factor (BDNF). Une étude subséquente, présentée dans le troisième article, nous a permis d’approfondir les bases génétiques et cellulaires du rôle du BDNF dans la persistance des symptômes post-commotionnels. Des polymorphismes fréquents dans le gène BDNF ont révélé des variantes liées au mauvais pronostic suite à un TCCL. De plus, l’analyse de cellules extraites de patients ayant subi un TCCL démontrent que l’expression de la protéine BDNF peut être modifiée chez le patient de génotype met66 et ayant subi un TCCL, lui conférant ainsi un rôle neuroprotecteur potentiel. En résumé, nous avons tenté de démontrer dans cette thèse que la douleur suite à un TCCL joue un rôle important dans les perturbations du sommeil et dans la persistance des symptômes post-commotionnels. Une prédisposition génétique pourrait contribuer à expliquer le mauvais pronostic et la chronicité des symptômes post-commotionnels suite à un TCCL. / Mild traumatic brain injury (MTBI) is a major public health concern as patients are left, amongst other symptoms, with sleep complaints and chronic pain. An interaction between these symptoms is suggested. For instance, a night of poor sleep is usually followed by hypersensitivity to pain and chronic pain always leads to sleep complaints. This interaction is suggested following an MTBI, however, data sustaining that hypothesis are still lacking. Data from the first article suggest that pain and other post-concussion symptoms are correlated with sleep-wake disturbances post-MTBI. MTBI patients with pain have more rapid electroencephalographic (EEG) waves during sleep than those without pain. This may suggest that there is an intrinsic physiological relationship between the two complaints. Moreover, pain seems to play an important role in the persistence of post-concussive symptoms. The second article of this thesis describes and details the exacerbation of post-concussive symptoms in the presence of pain following MTBI. The val66met polymorphism in the Brain-derived neurotrophic factor (BDNF) gene is an important predisposing factor for chronic pain. Lastly, a subsequent study, presented in the third article details the genetic and cellular basis of the role of BDNF in the persistence of post-concussive symptoms. Common polymorphisms in the BDNF genes were genotyped and revealed variants related to post-concussive symptoms following MTBI. Moreover, protein expression studies in lymphoblast cells of MTBI patients showed a modified expression of BDNF with the met genotype that might be neuroprotective. In summary, this thesis first shows that pain contributes to sleep-wake disturbances following MTBI and that the chronicity of post-concussive symptoms, including chronic pain, may be dependent on polymorphisms in the BDNF gene.

Following traumatic brain injury, there is an enhanced cell proliferative and neurogenic response in the young adult hippocampus, which may be associated with innate cognitive recovery. However, in the aged brain, an increased level of inflammatory cell responses was observed following injury concomitant to decreased hippocampal neurogenesis and cognitive recovery in the aging population. This suggests that excessive inflammation produced in the injured aging brain has a detrimental effect on neurogenesis and cognitive function. In this study, we examined the effect of anti-inflammatory treatment with minocycline on cell proliferation and generation of new neurons in the dentate gyrus (DG) of the hippocampus in both young and aged rats. Fisher 344 rats aged at 3 months and 20 months were subjected to a moderate lateral fluid percussion injury (LFPI) or cortical impact injury (CCI). Minocycline was administered intraperitoneally starting either at 30 minutes or 4 hours post-injury, thereafter twice daily for 2 days. BrdU was injected at 2 days post-injury to label injury-induced proliferating cells. To examine the effect of minocycline on cell proliferation, generation of new neurons, and inflammatory cell response at the acute stage post-injury, the rats were perfused 3 days post-injury. Brain sections were immunostained for BrdU and early neuronal marker doublecortin (DCX). The results show that short-term anti-inflammatory treatment with minocycline reduces the cell proliferative response, presumably inflammatory cell responses, in young and aged rats following LFPI and CCI injury, and enhances generation of new neurons in the hippocampus in both young and aged rats following LFPI and in aged rats following CCI injury. Therapies that enhance hippocampal neurogenesis may also have potential to improve cognitive recovery following TBI.

Traumatic brain injury is a major health problem with much of its morbidity associated with traumatic axonal injury (TAI). To date, significant insight has been gained into the initiating pathogenesis of TAI. However, the specific anterograde and retrograde sequelae of TAI are poorly understood because the diffuse nature of TAI complicates data analysis. To overcome this limitation, we subjected transgenic mice expressing yellow fluorescent protein (YFP) within the visual system to central fluid percussion injury, and consistently generated diffuse TAI within the optic nerve that could easily be followed in the organized YFP positive fibers. We demonstrated progressive axonal swelling, disconnection and proximal and distal axonal dieback, with regression and reorganization of the proximal swellings, and the persistence of the distal disconnected and degenerating swellings. Antibodies targeting the C-terminus of amyloid precursor protein, a marker of TAI, mapped to the proximal axonal segments without distal targeting. Antibodies targeting microglia/macrophages, revealed activated microglia/ macrophages closely encompassing the distal disconnected, degenerating axonal segments at 7 - 28 days post injury, suggesting their role in the delayed axonal degeneration. In contrast, in the proximal reorganizing axonal segments, microglia/macrophages appeared less reactive with their processes paralleling preserved axonal profiles. Concomitant with these events, YFP fluorescence quenching also occurred, complicating data analysis. This quenching mapped to Texas-Red-conjugated-IgG immunoreactive loci, suggesting that blood–brain barrier disruption and its attendant edema participated in fluorescence quenching. This was confirmed through antibodies targeting endogenous YFP, which identified the retention of intact axons despite YFP fluorescent loss. Paralleling these events, TAI was not accompanied by retrograde retinal ganglion cell (RGC) death. Specifically, no TUNEL+ or cleaved caspase-3 immunoreactive RGCs were observed from 2 days to 3 months post-TBI. Further, Brn3a immunoreactive RGC quantification revealed no significant RGC loss. This RGC preservation was accompanied by the persistent phospho-c-Jun expression for up to 3 months post-TBI, a finding linked to neuronal survival and potential axonal repair. Parallel ultrastructural study again failed to identify RGC death. Collectively, this study provides unprecedented insight into the evolving pathobiology associated with TAI, and offers advantages for future studies focusing on its therapeutic management and neuronal reorganization.

I. EFFECTS OF GLASGOW OUTCOME SCALE MISCLASSIFICATION ON TRAUMATIC BRAIN INJURY CLINICAL TRIALS The Glasgow Outcome Scale (GOS) is the primary endpoint for efficacy analysis of clinical trials in traumatic brain injury (TBI). Accurate and consistent assessment of outcome after TBI is essential to the evaluation of treatment results, particularly in the context of multicenter studies and trials. The inconsistent measurement or interobserver variation on GOS outcome, or for that matter, on any outcome scales, may adversely affect the sensitivity to detect treatment effects in clinical trial. The objective of this study is to examine effects of nondifferential misclassification of the widely used five-category GOS outcome scale and in particular to assess the impact of this misclassification on detecting a treatment effect and statistical power. We followed two approaches. First, outcome differences were analyzed before and after correction for misclassification using a dataset of 860 patients with severe brain injury randomly sampled from two TBI trials with known differences in outcome. Second, the effects of misclassification on outcome distribution and statistical power were analyzed in simulation studies on a hypothetical 800-patient dataset. Three potential patterns of nondifferential misclassification (random, upward and downward) on the dichotomous GOS outcome were analyzed, and the power of finding treatments differences was investigated in detail. All three patterns of misclassification reduce the power of detecting the true treatment effect and therefore lead to a reduced estimation of the true efficacy. The magnitude of such influence not only depends on the size of the misclassification, but also on the magnitude of the treatment effect. In conclusion, nondifferential misclassification directly reduces the power of finding the true treatment effect. An awareness of this procedural error and methods to reduce misclassification should be incorporated in TBI clinical trials. II. IMPACT OF MISCLASSIFICATION ON THE ORDINAL GLASGOW OUTCOME SCALE IN TRAUMATIC BRIAN INJURY CLINICAL TRIALS The methods of ordinal GOS analysis are recommended to increase efficiency and optimize future TBI trials. To further explore the utility of the ordinal GOS in TBI trials, this study extends our previous investigation regarding the effect of misclassification on the dichotomous GOS to examine the impact of misclassification on the 5-point ordinal scales. The impact of nondifferential misclassification on the ordinal GOS was explored via probabilistic sensitivity analyses using TBI patient datasets contained in the IMPACT database (N=9,205). Three patterns of misclassification including random, upward and downward patterns were extrapolated, with the pre-specified outcome classification error distributions. The conventional 95% confidence intervals and the simulation intervals, which account for the misclassification only and the misclassification and random errors together, were reported. Our simulation results showed that given a specification of a minimum of 80%, modes of 85% and 95% and a maximum of 100% for both sensitivity and specificity (random pattern), or given the same trapezoidal distributed sensitivity but a perfect specificity (upward pattern), the misclassification would have caused an underestimated ordinal GOS in the observed data. In another scenario, given the same trapezoidal distributed specificity but a perfect sensitivity (downward pattern), the misclassification would have resulted in an inflated GOS estimation. Thus, the probabilistic sensitivity analysis suggests that the effect of nondifferential misclassification on the ordinal GOS is likely to be small, compared with the impact on the binary GOS situation. The results indicate that the ordinal GOS analysis may not only gain the efficiency from the nature of the ordinal outcome, but also from the relative smaller impact of the potential misclassification, compared with the conventional binary GOS analysis. Nevertheless, the outcome assessment following TBI is a complex problem. The assessment quality could be influenced by many factors. All possible aspects must be considered to ensure the consistency and reliability of the assessment and optimize the success of the trial. III. A METHOD FOR REDUCING MISCLASSIFICATION IN THE EXTENDED GLASGOW OUTCOME SCORE The eight-point extended Glasgow Outcome Scale (GOSE) is commonly used as the primary outcome measure in traumatic brain injury (TBI) clinical trials. The outcome is conventionally collected through a structured interview with the patient alone or together with a caretaker. Despite the fact that using the structured interview questionnaires helps reach agreement in GOSE assessment between raters, significant variation remains among different raters. We introduce an alternate GOSE rating system as an aid in determining GOSE scores, with the objective of reducing inter-rater variation in the primary outcome assessment in TBI trials. Forty-five trauma centers were randomly assigned to three groups to assess GOSE scores on sample cases, using the alternative GOSE rating system coupled with central quality control (Group 1), the alternative system alone (Group 2), or conventional structured interviews (Group 3). The inter-rater variation between an expert and untrained raters was assessed for each group and reported through raw agreement and with weighted kappa (k) statistics. Groups 2 and 3 without central review yielded inter-rater agreements of 83% (weighted k¼0.81; 95% CI 0.69, 0.92) and 83% (weighted k¼0.76, 95% CI 0.63, 0.89), respectively, in GOS scores. In GOSE, the groups had an agreement of 76% (weighted k¼0.79; 95% CI 0.69, 0.89), and 63% (weighted k¼0.70; 95% CI 0.60, 0.81), respectively. The group using the alternative rating system coupled with central monitoring yielded the highest inter-rater agreement among the three groups in rating GOS (97%; weighted k¼0.95; 95% CI 0.89, 1.00), and GOSE (97%; weighted k¼0.97; 95% CI 0.91, 1.00). The alternate system is an improved GOSE rating method that reduces inter-rater variations and provides for the first time, source documentation and structured narratives that allow a thorough central review of information. The data suggest that a collective effort can be made to minimize inter-rater variation.

Traumatic brain injury (TBI) leads to short-term and long-term consequences that can cause many different life-long disorders. Studies of TBI have generally focused on the acute stage; however, it is now becoming important to investigate chronic responses following TBI as clinical reports of dementia and cognitive impairments have been linked to a history of TBI. Recent data have established that cognitive function is associated with hippocampal neurogenesis. Chronic injury induced changes in the brain may affect this endogenous process. Chronic responses following TBI include cell death pathways and inflammatory responses that are persistent in the brain for months to years after injury. In this study we investigate the chronic consequences of TBI on adult neurogenesis and the possible involvement of chronic-inflammation in regulating adult neurogenesis. We used two popular TBI animal models, Control Cortical Impact (CCI) and Lateral Fluid Percussion Injury (LFPI) models, to examine focal and diffuse injury responses respectively. Adult rats received CCI, LFPI, or sham injury and were sacrificed at either 15 days or 3 months after injury to examine either subacute or chronic TBI-induced responses respectively. We found no change in levels of proliferation activity at both time points in both TBI models compared to sham animals. Using Doublecortin immunolabeling we found an enhanced generation of new neurons at 15 days after injury and by 3 months this activity was significantly reduced in both TBI models compared to sham animals. We also found persistent inflammation in the injured brains at both time points. Morphological assessment showed that LFPI model of TBI causes shrinkage of the ipsilateral hippocampus. Our results show that moderate TBI induced hippocampal neurogenesis in both models at the early time post-injury. However, at chronic stage, reduced hippocampal neurogenesis is observed in both models and this is accompanied by chronic inflammation. These results suggest that persistent inflammatory responses maybe detrimental to normal neurogenic activity, leading to cognitive impairment and neurodegeneration in long-term TBI survivors.

Epidemiological data indicate that patients who experience a traumatic brain injury (TBI) have an elevated risk of developing a substance use disorder (SUD), but the underlying neurobiological connections remain unclear. To further understand the relationship between TBI and SUD, we investigated the effects of TBI on the abuse-related effects of oxycodone in preclinical models. Our evaluation utilized a lateral fluid percussion injury of moderate severity in adult male Sprague-Dawley rats. In the first aim, we tested the hypothesis that moderate TBI increases the risk for relapse to an opioid use disorder as measured by reinstatement of lever-pressing behavior following extinction in an intravenous oxycodone self-administration procedure. In the second aim, we tested the hypothesis that moderate TBI increases physiological dependence to oxycodone as measured by decreases in food-reinforced lever-pressing behavior and increases in other withdrawal behaviors in both precipitated withdrawal and spontaneous withdrawal. In tests for self-administration, brain-injured subjects, relative to non-injured subjects, showed no significant differences in the number of oxycodone-reinforced sessions required to meet stable maintenance criteria for lever-pressing behavior. Likewise, brain-injured subjects showed no significant differences in the number of non-reinforced sessions to meet extinction criteria for lever-pressing behavior relative to non-injured subjects. In tests for reinstatement, non-injured subjects reinstated responding under oxycodone-associated cue- and oxycodone prime-induced conditions, however, brain-injured subjects did not reinstate lever-pressing behavior under any conditions. In tests for physical dependence, brain-injured subjects showed no significant differences from non-injured subjects with regards to their mean withdrawal scores or food-reinforced lever-pressing behavior. Overall, these data suggest that brain-injured patients no significant pre-morbid history of opioid abuse are at a lesser risk of relapse to opioid use disorders. Moreover, the characteristic withdrawal syndrome in opioid-dependent patients may not contribute to continued opioid abuse to a greater degree in brain-injured patients than compared to non-injured patients.