Outcome after traumatic brain injury (TBI) depends on the extent of primary cell death and on the development of secondary brain injury. The general aim of this thesis was to find strategies and quality systems to minimize the extent of secondary insults in neurointensive care (NIC). An established standardized management protocol system, multimodality monitoring and computerized data collection, and analysis systems were used. The Uppsala TBI register was established for regular monitoring of NIC quality indexes. For 2008-2010 the proportion of patients improving during NIC was 60-80%, whereas 10% deteriorated. The percentage of ‘talk and die’ cases was < 1%. The occurrences of secondary insults were less than 5% of good monitoring time (GMT) for intracranial pressure (ICP) > 25 mmHg, cerebral perfusion pressure (CPP) < 50 mmHg and systolic blood pressure < 100 mmHg. Favorable outcome was achieved by 64% of adults. Nurse checklists of secondary insult occurrence were introduced. Evaluation of the use of nursing checklists showed that the nurses documented their assessments in 84-85% of the shifts and duration of monitoring time at insult level was significantly longer when secondary insults were reported regarding ICP, CPP and temperature. The use of nurse checklist was found to be feasible and accurate.  A clinical tool to avoid secondary insults related to nursing interventions was developed. Secondary brain insults occurred in about 10% of nursing interventions. There were substantial variations between patients. The risk ratios of developing an ICP insult were 4.7 when baseline ICP ≥ 15 mmHg, 2.9 when ICP amplitude ≥ 6 mmHg and 1.7 when pressure autoregulation ≥ 0.3. Hyperthermia, which is a known frequent secondary insult, was studied. Hyperthermia was most common on Day 7 after admission and 90% of the TBI patients had hyperthermia during the first 10 days at the NIC unit. The effects of hyperthermia on intracranial dynamics (ICP, brain energy metabolism and BtipO2) were small but individual differences were observed. Hyperthermia increased ICP slightly more when temperature increased in the groups with low compliance and impaired pressure autoregulation. Ischemic pattern was never observed in the microdialysis samples. The treatment of hyperthermia may be individualized and guided by multimodality monitoring.

Le traumatisme crânien (TC) représente un des problèmes majeurs de santé publique, pour lequel à l’heure actuelle il n’existe aucun traitement. Le TC induit une neuro-inflammation délétère qui pourrait contribuer à l’apparition des lésions de la substance blanche (SB). Ces dernières sont à l’origine de lourdes conséquences neurologiques chez les patients victimes de TC. Néanmoins, très peu d’études se sont intéressées à ces lésions bien que plus sévères que les lésions de la substance grise. Ainsi une meilleure connaissance de leur évolution et des causes devient indispensable. L’hyperactivation de la poly(ADP ribose)polymérase (PARP) joue un rôle délétère dans les conséquences post-traumatiques, notamment sur la neuro-inflammation. Ainsi son inhibition pourrait être bénéfique le développement des lésions de la SB. Dans ce contexte, l’objectif de notre travail a été d’évaluer le rôle de la PARP dans les lésions de la SB dans un modèle expérimental de TC induit par impact cortical contrôlé chez la souris. Dans une première partie, nous avons étudié l’évolution de la démyélinisation dans le corps calleux, une structure riche en SB, entre 6 heures et 3 mois post-TC. Parallèlement, les évolutions de la lésion cérébrale, des déficits sensorimoteurs, de la neuro-inflammation et de l’œdème cérébral ont été étudiées. Le TC induit (1) une démyélinisation dès 7 jours et au moins jusqu’à 3 mois post-TC, précédée par (2) une lésion cérébrale entre 24 et 72 heures suivie par une cicatrisation, (3) une neuro-inflammation entre 6 heures et 7 jours et (4) un œdème cérébral entre 6 et 72 heures post-TC. De plus, le TC induit des déficits sensorimoteurs à 6 heures et 3 mois. Ces résultats montrent que ce modèle est adapté pour étudier les lésions de la SB post-TC, et que la neuro-inflammation et l’œdème cérébral pourrait être impliqués dans la démyélinisation. Dans une deuxième partie, nous avons étudié le rôle de la PARP dans les lésions de la SB suite à TC à l’aide de souris knockout (KO) et wild-type (WT) pour le gène de la PARP. Nous avons mis en évidence que les souris KO ne présentent pas de démyélinisation bilatérale du corps calleux après un TC par rapport aux souris WT à 7 jours post-TC, démontrant pour la première fois l’implication de cette enzyme dans les lésions de la SB consécutives à un TC. De plus, nous avons constaté que les souris KO non traumatisées présentent une diminution de myélinisation comparativement aux souris WT non traumatisées, suggérant un rôle de la PARP dans le processus physiologique de la myélinisation.En conclusion, l’ensemble de ce travail expérimental a permis (1) une meilleure caractérisation de la démyélinisation post-TC et des mécanismes potentiellement impliqués dans cette dernière, et (2) de démontrer pour la première fois le rôle délétère de la PARP dans la démyélinisation induite par un TC. Nos travaux suggèrent le potentiel de l’inhibition de la PARP comme stratégie thérapeutique pour la prévention des lésions de la SB post-traumatiques. / Traumatic brain injury (TBI) is a leading cause of death and disability for which there is no neuroprotective treatment up to date. It results in neuroinflammation that may participate in lasting motor and cognitive impairments accompanied by changes in white matter (WM) tracts. WM lesions, evidenced by demyelination, are associated with neurological disorders and in clinical studies are common consequences in patients with chronic TBI. Several studies suggest a contribution of an overactivation of the poly(ADP-ribose) polymerase (PARP) to the neuroinflammatory response which may lead to demyelination. The first part of this study was dedicated to a detailed in vivo assessment of the evolution over time of neurological disorders, cerebral lesion and edema, neuroinflammation and white matter injury induced by controlled cortical impact (CCI) between 6 hours and 12 weeks post-TBI. Notably in the corpus callosum, a significant demyelination starting at 7 days appeared to be a major consequence to post-traumatic neuroinflammation associated with motor dysfunctions. The second part of this study was dedicated to the evaluation of PARP’s role in WM lesions post-TBI, using PARP knockout (KO) mice. Our main findings reveal a diminished demyelination in the corpus callosum of TBI PARP KO as opposed to TBI PARP wildtype specimens. Hence, these data suggest for the first time PARP’s deleterious role in post-traumatic demyelination. In conclusion, taken together these data give an overall view of motor/sensorimotor deficits, neuroinflammation and demyelination in a CCI model of TBI that could help to validate pharmacological strategy for preventing post-traumatic WM injury. Notably, PARP’s inhibition seems to be a valid candidate as this enzyme participates in the establishment of a demyelinating process.

Traumatic brain injury (TBI) results in over 50,000 deaths and 80,000 disabilities each year. Current treatment strategies aim to alleviate acute disturbances, but are not able to address the chronic disorders associated with TBI. Neural transplantation is one potential treatment that will provide multifaceted sustained therapy to degenerating injured tissue. Transplantation of multipotent neural stem cells (NSCs) has been shown to enhance functional recovery in TBI models; however, poor cell survival and integration with host tissue potentially restrict the efficacy of such transplants. This limitation may be due to the absence of inherent NSC pro-survival cues (e.g., cell-ECM interactions). Furthermore, the neural injury environment presents cell death factors to transplanted NSCs. It is hypothesized that a 3-D scaffold presenting specific CNS adhesive moieties will enhance donor cell survival and promote differentiation and migration. This project encompassed material development and in vitro characterization. Results highlighted the importance of ligand tethering chemistry and density and also the mechanical integrity of cell scaffold systems. Furthermore, the developed scaffold provides a controlled microenvironment to assess the influence of LN on NSC survival, migration, and differentiation. Lastly, co-delivering NSC with the MC-LN tissue engineered scaffold into a mechanically injured neural co-culture test-bed or in vivo TBI model confirmed the importance of ECM cues for NSC survival and migration, respectively.

There is limited knowledge of cognitive outcome extending beyond 5 years after childhood traumatic brain injury, CTBI. The main objectives of this thesis were to investigate cognitive outcome at 6-14 years after CTBI, and to evaluate if advancements in the neurosurgical care, starting 1992, did influence long-term outcome and early epidemiology. An additional aim was to study the relationship between early brain injury parameters and early functional outcome. Study 1 evaluated cognitive progress during 14 years after CTBI, over three neuropsychological assessments in 8 patients with serious CTBI. Study 2 used patient records to investigate early epidemiology, received rehabilitation and medical follow up in two clinical cohorts, n=82 and n=46, treated neurosurgically for CTBI before and after 1992. An exploratory cluster analysis was applied to analyse the relation between early brain injury severity parameters and early functional outcome. In Study 3, participants in the two cohorts, n=18 and n=23, treated neurosurgically for CTBI before and after 1992, were subject to an extensive neuropsychological assessment, 13 and 6 years after injury, respectively. Assessment results of the two cohorts were compared with each other and with controls. Data were analysed with multivariate analyses of variance. Results and discussion. There were significant long-term cognitive deficits of similar magnitude and character in the two cohorts with CTBI, treated before and after the advancements in neurosurgical care. At 6-14 years after injury, long-term deficits in verbal intellectual and executive functions were found, and were discussed in terms of their late maturation and a decreased executive control over verbal memory-functions after CTBI. Visuospatial functions had a slightly better long-term recovery. The amount of rehabilitation received was equally low in both cohorts. The length of time spent in intensive care and the duration of care in the respirator may have a stronger relationship to early outcome than does a single measure of level of consciousness at admission. Main conclusions are that cognitive deficits are apparent at long-term follow up, 6-13 years after neurosurgically treated CTBI, even after advancements in the neurosurgical care in Sweden. Measures of verbal IQ, verbal memory and executive functions were especially low while visuospatial intellectual functions appear to have a better long-term recovery. / At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.

Proteins offer a prominent group of compounds which may be ubiquitously affected in disease and used as biomarkers for early diagnosis, assessing treatment or drug development. Clinical proteomics aim to screen for protein biomarkers by a comprehensive analysis of all proteins expressed in a biological matrix during a certain pathology. Characterization of thousands of proteins in a complex biological matrix is from an analytical point of view a challenging task. Hence, sophisticated methods that are sensitive, specific and robust in a high-throughput manner are required. Mass spectrometry (MS) is able to perform this to a wide extent is. A prominent source for finding protein biomarkers related to neurological diseases is the central nervous system (CNS) due to close proximity of the pathogenesis. Neuroproteomic analysis of CNS tissue samples is thus likely to reveal novel biomarkers. Cerebrospinal fluid (CSF) bathes the entire CNS and offers a good balance between clinical implementation and usefulness. Both matrices put further requirements on the methodology due to a high dynamic range, low protein concentration and limited sample amount. The central objective of this thesis was to develop, assess and utilize analytical methods to be used in combination with MS to enable protein biomarker discovery in the CNS. The use of hexapeptide ligand libraries was exemplified on CSF from patients with traumatic brain injury and demonstrated the ability to compress the dynamic range to enable protein profiling in the order of mg/mL to pg/mL. Further, a method based on cloud-point extraction was developed for simultaneous enrichment and fractionation of hydrophobic/hydrophilic proteins in brain tissue. Comparison between label and label-free MS based strategies were carried out, mimicking the true conditions with a few differentially expressed proteins and a bulk of proteins occurring in unchanged ratio. Finally, a clinical application was carried out to explore the molecular mechanism underlying the analgesic effect of spinal cord stimulation (SCS) in patients with neuropathic pain. The CSF concentration of Lynx1 was found to increase upon SCS. Lynx1, acting as a specific modulator of the cholinergic system in the CNS, may act as a potential important molecular explanation of SCS-induced analgesia.

Previous research has shown that cognitive deficits arising from neurological impairment can impact on driving performance. The diverse nature of cognitive, perceptual and behavioural impairments experienced by drivers with neurological impairment and the resulting impact on driving ability has been the subject of extensive research involving the use of psychometric off-road measures, road safety statistics, actual on-road driving assessments and self-report. This research has shown that some drivers can compensate for limitations in their driving skills but this is dependent upon realistic self-appraisal of driving abilities. Few studies have investigated the role of self-awareness of driving abilities on on-road driving performance in persons with neurological impairment. Aims: To investigate the relationship between self-awareness of driving related abilities in neurologically impaired drivers and on-road driving performance. Participants: Retrospective data were collated on 79 participants who were referred for Occupational Therapy driving assessment, comprising 24 with Closed Head Injury (CHI) (mean age 24.67 + 5.57 yrs), 30 with Cerebrovascular Accident (CVA) (mean age 61.00 + 9.08 yrs) and 25 with 'Other' diagnosis (mean age 50.64 + 21.14 yrs). All participants held a current driver's licence or learner's permit Results: Five predictor variables were significantly associated with the on-road driving assessment outcome including three demographic variables:- diagnosis (2(2)= 7.69, p = 0.021), time since injury/illness onset (2(2)= 6.40, p = 0.041), and mileage (2(2)= 5.84, p = 0.05); and two self-awareness variables:- reaction time (2(2)= 8.04, p = 0.018), and impulse control (2(2)= 13.47, p = 0.001). Logistic regression yielded a final best model containing two predictor variables (2(4) = 20.81, p = 0.000), including diagnosis (p = 0.02) and self-awareness of impulse control (p = 0.01). Discussion and Conclusion: Participants who over-estimated their driving abilities were more likely to fail a driving assessment or require driving rehabilitation than participants who under-estimated or accurately predicted their performance and participants with a diagnosis of CVA were more likely to fail or require driving rehabilitation than those with a CHI or 'Other' diagnosis.

While the focus of rehabilitation following traumatic brain injury (TBI) is often on management of physical and cognitive impairments, emotional and behavioural changes in the person with the injury may represent major hurdles in adjustment following injury. Mood, anxiety and adjustment disorders are common following TBI. A manualised cognitive behavioural therapy (CBT) treatment programme was developed that incorporated provision of education on consequences of TBI, used cognitive and behavioural strategies to recognise and manage emotional reactions to injury, and promoted achievement of personal goals. Participants were nine people with TBI referred to Massey University Psychology Clinic Wellington, for psychotherapy to assist in managing symptoms of psychological distress or adjustment difficulties following injury. Measures used included the Hospital Anxiety and Depression Scale (HADS) to monitor progress in reduction of symptoms of Anxiety and Depression; the Patient Competency Rating Scale (PCRS) to assess competency across areas of day-to-day living; and the Homework Rating Scale Second Edition (HRS-II) to assess the value of homework assignments for participants. Results were presented graphically in group format and in the form of individual case studies outlining progress in achieving individual goals. There was considerable variation in the responses of participants to treatment. When anxiety and depression were secondary to other referral issues such as fatigue and pain that remained high over treatment sessions, there was limited movement on HADS Anxiety and Depression scores. The small number of participants impacted on the ability to detect differences between Patient and Informant ratings on the PCRS or to demonstrate increased levels of awareness over treatment sessions. Consistent completion of Homework assignments proved difficult for participants. Factors that impacted on achievement of personal goals included ongoing levels of fatigue and pain, levels of personal expectation, interpersonal and organisational skills, insight into emotional reactions, and good family and social support. There is a part for a CBT approach in adjusting to changes following TBI, particularly in assisting with reassessing expectations following injury.

The primary aim of the present study was to evaluate the effectiveness of the intervention provided by Massey University Concussion Clinic for individuals following Mild Traumatic Brain Injury (MTBI). Concussion Clinics were set up across New Zealand to provide early intervention and assessment for individuals with MTBI to prevent long term complaints. Treatment outcomes at these clinics have not been empirically examined before. The current study compared the levels of post concussion symptoms, anxiety, depression, and psychosocial functioning between an intervention and a control group using a quasi-experimental design. In addition, reasons for nonattendance to the clinic, and participants’ perceptions of their recovery were also explored. The main outcome measures used were the Rivermead Postconcussion Symptoms Questionnaire, the Hospital Anxiety and Depression Scale, and the Sydney Psychosocial Reintegration Scale-2. Outcomes were initially assessed soon after injury or referral to the clinic and then three months later. Participants were recruited from the Palmerston North Hospital Emergency Department and the Massey University Concussion Clinic. With 20 participants in the intervention group and 15 in the control group, the main results showed that the Concussion Clinic intervention significantly decreased the level of anxiety and depression reported by participants in the intervention group over the control group. Greater improvements in post concussion symptoms and psychosocial functioning were also indicated in the intervention group. Additional findings suggest difficulty with transportation as a reason for nonattendance, which could be a potential barrier to recovery. Furthermore, participants highlighted the benefits of attending the service and its role in their recovery. Important issues relating to the referral processes were also identified. Findings of the current study suggest that the Concussion Clinic intervention is effective in improving recovery for those accessing the service. Nevertheless, these results must be interpreted with caution due to the small sample size. Further research is warranted to examine the effectiveness of the Concussion Clinics with larger samples, and the current study may serve as a valuable pilot for these future investigations.

One of the goals of cognitive rehabilitation following traumatic brain injury is to help people perform everyday tasks. However, options for the rigorous assessment of everyday cognitive effectiveness after rehabilitation are limited. Performance on neuropsychological tests is only moderately correlated with everyday functioning, while previous measures of everyday functioning include only fairly general estimates of overall cognitive functioning. The aim of the current study was to develop an ecologically valid measure that captured a number of subdomains of executive functioning, using systematic behavioural observation of an everyday task. The initial phase of the research involved identifying an everyday task that was sufficiently complex to ensure that executive functioning was utilised in the completion of the task. Participants with traumatic brain injury were then asked to prepare chocolate brownies, using a recipe provided, and a hot drink. Participants were allowed to use any compensatory strategy to help complete the task. Participant performance was directly observed by an examiner and videotaped for subsequent inter-rater reliability. Two independent raters assessed nine components of executive functioning. During this phase, the examiner manuals were modified improving inter-rater reliability. The final version of the measure was then trialled with participants with and without traumatic brain injury. Final inter-rater reliability indicated the approach had merit. Significant and moderate correlations were found between traditional measures of executive functioning and the everyday task. This study employed systematic behavioural observation to obtain fine-grained information regarding a person’s cognitive functioning. With further development, this approach may prove useful for targeting and monitoring specific functional difficulties during cognitive rehabilitation.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Traumatic brain injury (TBI) is a major cause of morbidity and mortality in industrialized countries leading to the motor and cognitive deficits. Evidence demonstrated that exercise is neuroprotective in traumatic brain injury. However, the effects of exercise before of the TBI at the cognitive function are unknown. Role of excitotoxicity and oxidative damage in secondary damage of TBI, however, until this moment, were not demonstrated if exists a relationship between early phase of damage and the late cognitive deficit. In the current study, we proposed that improvement cognitive response induced by exercise prior in rats after a TBI can be associated with the neuroprotection of early phase after injury. To demonstrate this hypotheses, adult rats practice swimming exercise during 6 weeks followed for TBI operation. We assessed the motor alterations of early phase, the glutamate uptake and antioxidant defense in twenty four hours (24 h) and 15 days after TBI. Acquisition of memory was assessed by recognition object task on days 15 post TBI. Moreover, we evaluated the brain-derived neurotrophic factor (BDNF) to assessement the synaptic plastic. In the present study, we showed that TBI induced by fluid percussion injury (FPI) in adult male Wistar rats induced early motor impairment 24 h, followed by learning retention deficit (2 weeks after neuronal injury). Previous swimming training improved the memory in object recognition task per se and protected against FPI-related disabilities. Although the FPI did not alter hippocampal expression of glutamate transporters (EAAT1 / EAAT2) and brain-derived neurotrophic factor (BDNF), the alterations in the redox status, herein characterized by DCFH-DA oxidation and SOD activity inhibition, led to marked impairment of protein functionally (Na+, K+-ATPase activity inhibition) and glutamate uptake inhibition 24 h after neuronal injury in sedentary injured rats. Indeed, the early increase of nuclear factor erythroid 2-related factor (pNRF2/NRF2 ratio) followed by a repair mechanism (protein HSP70 expression), 24 h and 2 weeks after neuronal injury, suggests that FPI-induced signal transduction may exert compensatory effect on pathophysiological processes. In this report we showed that previous physical exercise induced the increase of immune content of glutamate transporters (EAAT1/ EAAT2), pNrf2/Nrf2 ratio, SOD enzyme and HSP70 per se besides preventing against FPI-induced Na+, K+ - ATPase activity, glutamate uptake inhibition DCFH-DA oxidation 24 h after neuronal injury. The enhancement of hippocampal pNrf2/Nrf2 and HSP70 immune content in trained injured when compared with sedentary rats suggest that protein expression modulation associated to antioxidant defense elicited by previous physical exercise prevent against toxicity induced by TBI. The significant increase of BDNF levels in trained injured rats 24 h and 2 weeks strongly reinforce the idea that physical activity alters neuronal functions and thus delays or prevents secondary cascades that leave the neurobehavioral disability after TBI. / O traumatismo cranioencefálico (TCE) é uma das maiores causas de morte e morbidade nos países industrializados podendo levar ao comprometimento motor e déficits cognitivos. Evidências demonstram que o exercício físico é neuroprotetor na recuperação após o TCE. Porém, os efeitos do exercício físico antes do TCE na função cognitiva não são totalmente conhecidos. Sabe-se da participação da excitotoxicidade e do estresse oxidativo na cascata do dano secundário após o TCE, entretanto até o momento não foi demonstrado qual a relação da fase inicial após o TCE com os déficits cognitivos tardios. Portanto, no presente estudo, nós propomos que a melhora cognitiva tardia induzida pelo exercício prévio em ratos após o TCE pode estar associada com a neuroproteção da fase inicial após o dano. Para demonstrar esta hipótese, ratos adultos praticaram treinamento de natação durante 6 semanas e posteriormente foram submetidos a cirurgia para o TCE. Nós avaliamos as alterações motoras iniciais, a captação de glutamato e a defesa antioxidante em 24 horas (24 h) e 15 dias após o TCE. Aquisição da memória foi avaliada pela tarefa de reconhecimento de objetos em 15 dias após o TCE. Além disso, nós avaliamos o fator neurotrófico derivado do encéfalo (BDNF) para avaliar a plasticidade sináptica. No presente estudo, nós mostramos que o TCE induzido pela lesão de percussão de fluido (LPF) em ratos Wistar machos adultos induziu déficit motor inicial 24 h, seguido por déficit de aprendizagem (15 dias após o dano neuronal). O treinamento de natação prévio melhorou a memória na tarefa de reconhecimento de objeto per se e protegeu contra desabilidades relacionadas ao LPF. Embora o LPF não tenha alterado a expressão dos transportadores de glutamato (EAAT1/EAAT2) e de BDNF, causou uma alteração no estado redox, caracterizado pela oxidação de DCFH-DA e inibição da atividade da SOD. O LPF também causou prejuízo acentuado da funcionalidade de proteínas (inibição da atividade da enzima Na+, K+-ATPase) e inibição da captação de glutamato 24 h após o dano neuronal em ratos sedentários lesionados. De fato, o aumento inicial do fator de transcrição Nrf2 (relação pNrf2/Nrf2), 24 h após o TCE, seguido por um mecanismo de reparo (expressão da proteína Hsp70), 24 h e 15 dias após o dano neuronal, sugerem que a transdução de sinal induzida pelo LPF pode exercer um efeito compensatório em processos patofisiológicos. Neste trabalho, nós mostramos que o exercício físico prévio induziu o aumento do imunoconteúdo dos transportadores de glutamato (EAAT1/EAAT2), relação pNrf2/Nrf2, enzima SOD e a proteína Hsp70 per se, além de prevenir contra inibição da atividade da Na+, K+-ATPase, inibição da captação de glutamato e oxidação de DCFH-DA induzida pelo LPF, 24 h após o dano neuronal. O aumento do imunoconteúdo hipocampal de pNrf2/Nrf2 e Hsp70 em ratos treinados e lesionados quando comparado com ratos sedentários, sugerem que a modulação da expressão das proteínas associadas às defesas antioxidantes induzidas pelo exercício físico prévio preveniu contra a excitotoxicidade induzida pelo TCE. O significante aumento nos níveis de BDNF em ratos treinados e lesionados 24 h e 15 dias, reforçam fortemente a ideia que a atividade física altera a função neuronal e assim retarda ou previne as cascatas do dano secundário que levam a desabilidade neuronal após o TCE.