Traumatic axonal injury (TAI) contributes to the mortality and morbidity following diffuse traumatic brain injury (TBI). Previous work has shown that following TBI, alterations in the molecular domains of axons result in TAI. It is currently posited that injury induced ionic flux is responsible for activating deleterious proteolytic cascades, resulting in altered distributions of axonal components. However, the underlying mechanism of this progressive pathology remains elusive. This study further explores the hypothesis that altered molecular domains contributes to the progressive intra-axonal changes that characterize TAI. Using a rodent model of impact acceleration TBI we examined the expression of nodal and paranodal domains of myelinated axons in brainstem over a 24 h period post-injury. Western blot analysis was utilized to quantify changes in protein levels of Nav1.6, a prominent component at the node of Ranvier, and Caspr, a constituent of the paranodal tripartite complex. Here we report that diffuse TBI causes an up-regulation of Nav1.6 and a down-regulation of Caspr over a 24 h time-course post-injury. The results of this study support that alterations in the molecular components of the domains of injured axons contribute to the cellular mechanism of TAI and thus provides novel data in the field of TBI research.

It is estimated that there are 12.5 million people in England living with neurological disorders (Neurological Alliance, 2014). People with neurological disorders as a result of acquired brain injury (ABI) are living with short and long-term disabilities. These include cognitive impairment, and physical and emotional distress. One of the most common complaints by individuals who have ABI is attention impairment. Attention difficulties can have serious ramifications for daily functioning. Although studies have explored the effects of evidence-based interventions such as mindfulness-based therapy on attention abilities, and have found that it improves individuals' attention skills (Moore et al, 2012), thus far research has been conducted mainly with non-clinical populations. This study set out to investigate whether a mindfulness-based intervention could prove beneficial for people with neurological disorders, particularly whether it could positively impact on attention impairment. The study employed a one group pre-test post-test design. The intervention was adapted from the MBSR programme developed by Kabat-Zinn. Twenty-two participants with ABI were recruited. The Conners Continuous Performance Test 3rd Edition (CPT-3), Mindful Attention Awareness Scale (MAAS), Attention Process Training-II Attention Questionnaire (APT-II AQ) and Clinical Outcome in Routine Evaluation-Outcome Measure (CORE-OM) were utilised to measure outcomes. The results revealed that there was a clinical improvement in self reported measures of mindfulness (MAAS) (Cohen d=0.28), attention (APT-II AQ) (Cohen d=0.33), and psychological distress (CORE-OM) (Cohen d=0.72). This was not observed using the neuropsychological test of attention (CPT-3) for overall group scores, but further evaluation showed some individuals' scores improved. The study is promising as it indicates that mindfulness based treatment can be effective with attentional problems as well as in reducing psychological distress for individuals with ABI. This could be valuable in terms of providing treatment for this client group and adds to the expanding research base on mindfulness-based intervention with this population.

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.

Introduction: Mild traumatic brain injury (mTBI) accounts for the vast majority of all paediatric TBI cases. It is an important public health concern, yet the long-term psychiatric and behavioural outcomes remain imperfectly understood. Aim. This study aims to examine the association between paediatric mTBI and psychiatric and offending outcomes in adulthood, while considering the impact of sex, age at injury and duration since injury on outcome. Participants: Participants with mTBI (n=57) were compared to those with moderate/severe TBI (n=62) and to orthopaedic injury controls (n=42). All participants were injured at age 17 or younger and were 18 years or older at the time of assessment. Outcome measures: Based on the DSM-IV-TR criteria, structured interviews were used to assess participants’ experience of symptoms consistent with major depressive disorder, anxiety disorders (including generalised anxiety disorder, panic attacks and panic disorder, agoraphobia, social phobia, post-traumatic stress disorder, and specific phobia), and substance abuse and/or dependence. Participants’ were asked to report on their lifetime involvement with offending, arrests, and diversions and/or convictions. Results: At age 18-31, participants with a paediatric mTBI were significantly more likely than orthopaedic injury controls to endorse symptoms consistent with major depressive disorder by 3.17 times, anxiety disorders by 5.81 times, and internalising disorders in general by 5.80 times and the risk in the mTBI group was greater than that for those with moderate/severe TBI. Females with mTBI were significantly more likely than males, by five times, to endorse an internalising disorder. Paediatric mTBI was not significantly associated with externalising problems when compared with controls; however, males with mTBI were 6.57 times more likely to endorse externalising behaviours than females. Conclusions: Paediatric mTBI is a risk factor for internalising disorders in adulthood, particularly for females. Such findings have implications for assessment and treatment of problems associated with paediatric mTBI.

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.

Research into traumatic brain injury (TBI) mechanisms is essential for the development of methods to prevent its occurrence. One of the most common ways to incur a TBI is from falls, especially for the young and very old. The purpose of this thesis was to investigate how the acceleration loading curves influenced the occurrence of different types of TBI, namely: epidural hematoma, subdural hematoma, subarachnoid hemorrhage, and contusion. This investigation was conducted in three parts. The first study conducted reconstructions of 20 TBI cases with varying outcomes using MADYMO, Hybrid III, and finite element methodologies. This study provided a dataset of threshold values for each of the TBI injuries measured in parameters of strain and stress. The results of this study indicated that using a combined reconstructive approach produces results which are in keeping with the literature for TBI. The second study examined how the characteristics of the loading curves which were produced from each reconstruction influenced the outcome using a principal components analysis. It was found that the duration of the event accounted for much of the variance in the results, followed with the acceleration components. Different curve characteristics also accounted for differing amounts of variance in each of the lesion types. Study 3 examined how the dynamic response of the impact influenced where in the brain a subdural hematoma (SDH) could occur. It was found that the largest magnitudes of acceleration produced SDH in the parietal lobe, and the lowest in the occipital lobe. Overall this thesis examined the mechanism of injury for TBI using a large dataset with methodologies which complement each other’s limitations. As a result in depth information of the nature of TBI was attained and information provided which may be used to improve future protection and standard development.

xii, 98 p. : ill. (some col.) / The short and long term pathophysiology of traumatic brain injury (TBI) has not been fully elucidated. Individuals recently suffering a mild TBI (mTBI) or having a history of TBI frequently suffer deficits in their ability to maintain and allocate attention within and between tasks. This dissertation examines the influence of mild and chronic TBI on performance of task switching. We employed spatial and numerical task switching paradigms to assess the behavioral deficits in mTBI, and we used an internally generated switching and an externally cued switching task along with functional Magnetic Resonance Imaging (fMRI) to assess the long term deficits in executive function resulting from chronic TBI. In the first experiment, individuals with mTBI were identified and tested within the first 48 hours of injury and then at a set interval 5, 14, and 28 days post injury. In the second investigation, individuals with chronic TBI were tested at least 12 months after their most recent injury. Healthy gender, age, and education matched controls were also tested in both studies. This research demonstrated that mTBI subjects display deficits in switching behavior within 48 hours of injury that failed to resolve a month post-injury; however, these costs did not generalize across the switching task types. Chronic TBI subjects performed internally generated and externally cued switching paradigms with a degree of success equivalent to that of healthy controls but displayed larger amounts of activation and recruited more areas of the brain at lower levels of difficulty and did not increase recruitment in a stepwise fashion at higher levels of difficulty. Mild TBI causes significant deficits in task switching, but there is specificity in these deficits. Chronic TBI patients performed at a level equivalent to that of controls but displayed different patterns and degree of activation. Taken together, these findings indicate that there may be a specific time frame during which task switching shows behavioral deficits, after which the subject may compensate for these deficits to produce normalized performance. / Committee in Charge: Dr. Paul van Donkelaar, Chair; Dr. Li-Shan Chou; Dr. Ulrich Mayr; Dr. Marjorie Woollacott

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / In humans, intracranial hypertension (ICH) disturbs cardiovascular function and also modifies gastrointestinal physiology as clinically manifested by nausea and vomiting symptoms. Since gastric compliance drives the gastric emptying of liquid which is inhibited by ICH, it was studied the ICH effect on gastric compliance behavior in anesthetized rats and the neuropathways possibly serving this phenomenon. Anesthetized male Wistar rats (N=65, 280-320g) received a carotid cannula to monitor arterial pressure (AP) and heart rate (HR). Under stereotactic guidance a cannula was positioned into each lateral ventricule: one for cerebrospinal fluid simile infusion and the other to record intracranial pressure (ICP in mmHg). All animals received a catheter balloon that was positioned in the proximal stomach and connected to a U shaped barostat filled with standard ionic solution set 4cm above the animals xyphoid appendix. Gastric volume changes transmitted to this communicant vessel system were sensed and recorded by a plethysmometer for 80min After a basal period of 20min the animals were randomly allocated to either experimental protocols: control or ICH. In controls the animals remained untouched while in ICH the ICP was increased from basal to 10, 20, 40, or 60 mmHg, for 30min. In crescent ICP, the pressure was increased in the same animal, at every 20min, from basal to 20, 40 and then 60 mmHg. Separate groups of animals also underwent neurotomy or respective sham operation: subdiafragmatic vagotomy, splancnotomy plus bilateral ganglionectomy and after the basal period were submitted to 10 mmHg of ICP. Brains from other animals (control ICP 10 and ICP 60 mmHg) were removed for histological studies. Data (mean  SEM) were compared to respective basal values after ANOVA and Bonferroniâs test. In controls, hemodynamic parameters and GV remained within stable levels. In ICP 10 mmHg, GV decreased (P<0.05) from basal levels (2.70Â0.12ml) to 2.30Â0.14ml at 30min to remain decreased afterwards, while at ICP 20, 40 and 60mmHg decreased early at 20min of ICH (2.36Â0.18 vs 2.03Â0.19, 2.69Â0.27 vs 2.03Â0.25 e 2.83Â0.12 vs 1.95Â0.11ml, respectively), remaining as such up to the end (P<0.05). In crescent ICP, GV decreased from basal levels (2.94Â0.04ml) at ICP 40mmHg to 2.70Â0.07ml as well as at ICP 60 mmHg to 2.67Â0.06ml (P<0.05). In all groups were observed arterial hypertension and bradycardia, typical findings of Cushingâs reflex. In animals without vagal connection, GV despite beginning from lower basal values (1.82Â0.18ml) decreased (P<0.05) at 30min to 1.69Â0.18ml. After sympathectomy, GV remained stable (P>0.05) throughout the experiment (2.29Â0.21ml vs 2.11Â0.23ml). Moderate meningeal edema-coroid plexus- was observed moreover at brains from ICP 60mmHg subset. In conclusion, experimental ICH besides inducing Cushingâs reflex (arterial hypertension and bradycardia) also decreases gastric compliance in anesthetized rats in an ICP dependent manner. Vagotomy had no effect and this phenomenon is likely to be mediated by sympathetic neuropathways. / Em humanos, a hipertensÃo intracraniana (HIC) alÃm de promover distÃrbios hemodinÃmicos, tambÃm provoca alteraÃÃes na funÃÃo gastrintestinal, apresentadas clinicamente com nÃuseas e vÃmitos. Como a HIC em ratos acordados inibe o esvaziamento gÃstrico de lÃquido e este à influenciado pela complacÃncia gÃstrica (CG), estudou-se o efeito da HIC sobre a CG e os mecanismos neurais envolvidos no fenÃmeno. Ratos Wistar (N=65, 280-320g) anestesiados com uretana tiveram a artÃria carÃtida canulada para registro hemodinÃmico. Mediante estereotaxia, cÃnulas-guias foram implantadas bilateralmente nos ventrÃculos laterais, para registro simultÃneo da PIC e compressÃo do sistema ventricular por infusÃo de lÃquido cefalorraquidiano-sÃmile (LCR-sÃmile). Um catÃter com um balÃo na extremidade foi posicionado no estÃmago proximal e conectado a um sistema de vasos comunicantes com barostato. VariaÃÃes do volume do balÃo gÃstrico (VG) transmitidas ao barostato foram detectadas por um sensor eletrÃnico de volume e registradas continuamente por 80min num pletismÃmetro. ApÃs um perÃodo basal de 20min, os ratos foram aleatoriamente submetidos Ãs seguintes condiÃÃes: Controle (PIC espontÃnea), PIC 10mmHg, PIC 20mmHg, PIC 40mmHg, PIC 60mmHg e PIC Crescente. ApÃs a compressÃo ventricular, os animais foram monitorados por mais 30min. Para o estudo dos mecanismos neurais, grupos de ratos, previamente submetidos a laparotomia seguida ou nÃo (falsa cirurgia) de vagotomia subdiafragmÃtica ou esplancnicectomia+gangliectomia celÃaca bilaterais, foram estudados sob PIC de 10mmHg. Um grupo à parte de animais (n=9) PIC controle, PIC 10mmHg e PIC 60mmHg tiveram seus encÃfalos retirados para avaliaÃÃo histolÃgica. Os dados foram expressos em mÃdiaÂEPM e analisados pela ANOVA seguido pelo teste de Bonferroni. No grupo controle, os parÃmetros hemodinÃmicos e de VG se mantiveram constantes. No grupo PIC 10mmHg, em relaÃÃo ao perÃodo basal (2.70Â0.12ml), o VG diminuiu para 2.30Â0.14ml aos 30min de HIC, assim permanecendo por todo o experimento (P<0.05). Jà nos grupos PIC 20mmHg, PIC 40mmHg e PIC 60mmHg, o VG diminuiu em relaÃÃo ao perÃodo basal aos 20min de HIC (2.36Â0.18 vs 2.03Â0.19, 2.69Â0.27 vs 2.03Â0.25 e 2.83Â0.12 vs 1.95Â0.11ml, respectivamente), assim permanecendo atà o final (P<0.05). No grupo PIC crescente, em relaÃÃo ao perÃodo basal (2.94Â0.04ml), o VG diminuiu para 2.70Â0.07ml com PIC 40 mmHg e para 2.67Â0.06ml com PIC 60mmHg (P<0.05). Em todos os grupos observou-se hipertensÃo arterial e bradicardia, efeitos tÃpicos do reflexo de Cushing. Nos animais sem conexÃo vagal, o VG embora partindo de nÃveis basais menores (1.82Â0.18ml) diminuiu (P<0.05) aos 30min para 1.69Â0.18ml. Nos animais submetidos a esplacnicectomia, em relaÃÃo ao perÃodo basal (2.29Â0.21ml), o VG permaneceu inalterado (P>0.05) durante (2.11Â0.23ml) e apÃs a compressÃo ventricular. Nas lÃminas analisadas identificou-se edema parenquimatoso e congestÃes menÃngea, do plexo corÃide e parenquimatosa de graus leve a moderado, principalmente nos animais submetidos a PIC de 60 mmHg. A HIC diminui a CG de ratos anestesiados, sendo o fenÃmeno PIC dependente e possivelmente mediado por via esplÃncnica

Research into traumatic brain injury (TBI) mechanisms is essential for the development of methods to prevent its occurrence. One of the most common ways to incur a TBI is from falls, especially for the young and very old. The purpose of this thesis was to investigate how the acceleration loading curves influenced the occurrence of different types of TBI, namely: epidural hematoma, subdural hematoma, subarachnoid hemorrhage, and contusion. This investigation was conducted in three parts. The first study conducted reconstructions of 20 TBI cases with varying outcomes using MADYMO, Hybrid III, and finite element methodologies. This study provided a dataset of threshold values for each of the TBI injuries measured in parameters of strain and stress. The results of this study indicated that using a combined reconstructive approach produces results which are in keeping with the literature for TBI. The second study examined how the characteristics of the loading curves which were produced from each reconstruction influenced the outcome using a principal components analysis. It was found that the duration of the event accounted for much of the variance in the results, followed with the acceleration components. Different curve characteristics also accounted for differing amounts of variance in each of the lesion types. Study 3 examined how the dynamic response of the impact influenced where in the brain a subdural hematoma (SDH) could occur. It was found that the largest magnitudes of acceleration produced SDH in the parietal lobe, and the lowest in the occipital lobe. Overall this thesis examined the mechanism of injury for TBI using a large dataset with methodologies which complement each other’s limitations. As a result in depth information of the nature of TBI was attained and information provided which may be used to improve future protection and standard development.