This study looked in detail at the parental experience of having a child sustain traumatic brain injury (TBI); beginning with the child sustaining the injury, through the acute and chronic stages of rehabilitation, to the child’s return home. Mother and father dyads were interviewed in their own homes using a semi-structured interview schedule. A narrative analysis highlighted important findings through the identification and construction of several plots and subplots within parent narratives. These include that parents themselves appear to undergo trauma as a consequence of their child sustaining TBI; that parents made - and wanted to make - a major contribution throughout their child’s rehabilitation, and that all parents went - and are continuing to go - through a number of transitions in this process. Given that fathers have historically been neglected from research into child health issues, the finding here that mothers and fathers made a substantial contribution throughout the rehabilitation process is timely and important. For most parents, this event led to profound and long-lasting changes in their lives and life stories where their previous, hitherto narratives were ‘shattered’. On the child’s return home, these changes appear neither recognised nor supported by services. There seemed little if anything in service provision and coordination to meet the needs of children and parents, which resulted in parents continually fighting for services. Clinical implications are discussed as well as directions for future research.

Background: For Diffusion Tensor Imaging (DTI) to become a clinically useful tool in the detection of traumatic brain injury (TBI) and prediction of functional outcome, a reliable method enabling the identification of likely injury in individual patients needs to be developed. Objective: To explore different methods of analysing DTI measures to determine if individual TBI patients can be differentiated from a group of non-brain injured controls and if so, how these differences are associated with cognitive function. Method: 4 participants with TBI and 11 control participants were scanned using DTI and completed a battery of neuropsychological tests. The DTI measures of Fractional Anisotropy (FA) and Mean Diffusivity (MD) in the uncinate fasciculus were compared across individual TBI patients and a control group using 3 different methods of analysis. Results: The comparison of mean FA/MD from individual TBI patients with the overall mean FA/MD of the control group revealed that some TBI patients had lower values of FA whilst others had increased MD. This difference in FA may be associated with deficits in measures of attention. The histogram curves and cumulative frequency plots for individual TBI patients and the controls revealed subtle yet potentially significant differences in the distribution of FA/MD. However at this stage these differences could not be associated with cognitive function. Conclusion: Initial findings indicate that individual TBI patients can be differentiated from a control group using different methods with differing degrees of sensitivity. These differences may be related to cognitive function but further research is warranted before firm conclusions can be drawn.

Background Traumatic brain injury (TBI) is a complex disease with a spectrum of symptoms and disabilities. Over the past decade TBI has become the focus of research due to growing epidemiological and clinical evidences that TBI incidences are strong risk factors for Alzheimer’s disease (AD). Major pathological hallmarks of AD are massive accumulations of amyloid-β peptide (Aβ) toxic oligomers and plaques. Neuroinflammation is also considered as a common denominator in AD and aging. The epidemiological and experimental studies have supported that non-steroidal anti-inflammatory drugs markedly reduce the age-related prevalence of AD and can slow amyloid deposition by mechanisms that still remain elusive. S100A9 is a multifunctional cytokine with diverse roles in the cell signaling pathways associated with inflammation and cancers. A widespread expression of S100A9 was also reported in many other ailments involving inflammatory processes, such as AD, malaria, cerebral ischemia and TBI, implying that S100A9 may be a universal biomarker of inflammation. The distinctive feature of S100A9 compared to other pro-inflammatory cytokines is its ability to self-assemble into amyloids, which may lead to the loss of its signaling functions and acquired amyloid cytotoxicity, exceeding that of Aβ. Methods S100A9 properties was studied under various ex vivo and in vitro conditions. First, human and mouse tissues with TBI and AD were subjected to microscopic, immunohistochemical and immunofluorescent techniques. Then, aged mouse treated with native, oligomeric and fibrillary S100A9 was also studied by using behavioral and neurochemical analysis. Moreover, S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ42 and tau proteins, by studying cerebrospinal fluid (CSF) samples from different stages of dementia. Finally, in vitro experiments on S100A9 amyloidogenesis, co-aggregation with Aβ40 and Aβ42, digestion and cytotoxicity were also performed by using spectroscopic, atomic force microscopy and cell biology methods. Results S100A9-driven amyloid-neuroinflammatory cascade serves as a link between TBI and AD. We have found that S100A9 contributes to the plaque formation and intraneuronal responses in AD, being a part of the amyloid-neuroinflammatory cascade. In TBI we have found that extensive S100A9 neuronal production and amyloid self-assembly is triggered immediately after injury, leading to apoptotic pathways and neuronal loss. S100A9 is an integral component of both TBI precursor-plaques, formed prior to Aβ deposition, and AD plaques, characterized by different degree of amyloid maturation, indicating that all plaques are associated with inflammation. Both intra- and extracellular amyloid-neuroinflammatory cascades are intertwined and showed similar tendencies in human and mouse tissues in TBI and AD. Ex vivo findings are further supported by in vitro experiments on S100A9 amyloidogenesis, digestion and cytotoxicity. Importantly, being highly amyloidogenic itself, S100A9 can trigger and aggravate Aβ amyloid self-assembly and significantly contribute to amyloid cytotoxicity. Moreover, the CSF dynamics of S100A9 levels matches very closely the content of Aβ42 in AD, vascular dementia and mild cognitive impairment due to AD, emphasizing the involvement of S100A9 together with Aβ in the amyloid-neuroinflammatory cascade in these ailments. Conclusions The conclusions of this thesis is that the inflammatory pathways and S100A9 specifically represent a potential target for the therapeutic interventions during various post-TBI stages and far prior AD development to halt and reverse these damaging processes. / Role of pro-inflammatory S100A9 protein in amyloid-neuroinflammatory cascade in Alzheimer’s disease and traumatic brain injury

In the pathophysiology of traumatic brain injury (TBI), the amygdala remains understudied, despite involvement in processing emotional and stressful stimuli associated with anxiety disorders, such as post-traumatic stress disorder (PTSD). Because the basolateral amygdala (BLA) integrates inputs from sensory and other limbic structures coordinating emotional learning and memory, injury-induced changes in circuitry may contribute to psychiatric sequelae of TBI. This study quantified temporal changes in dendritic complexity of BLA neurons after experimental diffuse TBI, modeled by midline fluid percussion injury. At post-injury days (PIDs) 1, 7, and 28, brain tissue from sham and brain-injured adult, male rats was processed for Golgi, glial fibrillary acidic protein (GFAP), or silver stain and analyzed to quantify BLA dendritic branch intersections, activated astrocytes, and regional neuropathology, respectively. Compared to sham, brain-injured rats at all PIDs showed enhanced dendritic branch intersections in both pyramidal and stellate BLA neuronal types, as evidenced by Sholl analysis. GFAP staining in the BLA was significantly increased at PID1 and 7 in comparison to sham. However, the BLA was relatively spared from neuropathology, demonstrated by an absence of argyrophilic accumulation over time, in contrast to other brain regions. These data suggest an early and persistent enhancement of dendritic complexity within the BLA after a single diffuse TBI. Increased dendritic complexity would alter information processing into and through the amygdala, contributing to emotional symptoms post-TBI, including PTSD.

The ability of the brain to keep a stable and adequate cerebral blood flow (CBF) independently of fluctuations in systemic blood pressure is referred to as cerebral pressure autoregulation (CPA). When the brain is injured by trauma or hemorrhage, this ability may be impaired, leaving the brain vulnerable to events of high or low blood pressure. The aims of this thesis were to study CPA in patients with severe traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH), the relation between CPA and other physiological parameters, and the influence of CPA on outcome. Four retrospective studies are included in the thesis. All patients were treated at the neurointensive care unit, Uppsala University hospital. In paper I, 58 TBI patients were studied. In patients with impaired CPA, cerebral perfusion pressure between 50-60 mm Hg was associated with favorable outcome while CPP > 70 and >80 mm Hg was associated with unfavorable outcome. In patients with intact CPA there was no association between CPP and outcome. In paper II, 107 TBI patients were studied. High CPP was associated with unfavorable outcome in patients with focal injuries. In patients with diffuse injury and impaired CPA, CPP > 70 mm Hg was associated with favorable outcome. In paper III, 47 SAH patients were studied. CBF was measured bedside with Xenon-enhance CT (Xe-CT). Patients with impaired CPA had lower CBF, both in the early (day 0-3) and late (day 4-14) acute phase of the disease. In paper IV, 64 SAH patients were studied. Optimal CPP (CPPopt) was calculated automatically as the level of CPP where CPA works best for the patient, i.e., where PRx is lowest. Patients with actual CPP below their calculated optimum had higher amounts of low-flow regions (CBF < 10 ml/100g/min). The findings in this thesis emphasize the importance of taking CPA into account in the management of TBI and SAH patients, and suggest that treatment should be individualized depending on status of autoregulation. PRx and CPPopt may be used bedside to guide management according to status of autoregulation. In the future CPA-guided management should be tested in prospective studies

Prior evidence has shown a reduction of neglect on line bisection tasks as a function of altered hemispace presentation and left cueing. The present study was conducted to examine the effect of these factors in reducing symptoms of neglect on measures of general cognitive functioning. To examine proposed changes, revised versions of the Raven's Coloured Progressive Matrices and the Memory-for-Designs (MFD) Test were constructed by placing the target stimuli in the right hemifield. Two experimental presentations, a right hemispace condition and a right hemispace plus left cue prompt condition, were compared to the standard presentation format. The primary hypotheses predicted that RBD neglect patients would reveal enhanced performance on the criterion measures as a result of these manipulations. Significant correlations were predicted between the neglect measures and between the two scoring systems for the MFD. The sample was comprised of 54 hospitalized patients, assigned to either a RBD neglect group (N = 18), a RBD nonneglect group (N = 18) , or an orthopedic control group (N = 18) . Both RBD groups were administered the Mini Inventory of Right Brain Injury, to document the presence and severity of right brain injury. Presence of neglect was assessed via the Schenkenberg Line Bisection Task and the Bells Test for Visual Neglect. Subjects were examined under all three conditions by administering one third of the items for each condition. Neglect subjects demonstrated significantly poorer performance on both criterion measures than the two comparison groups. However, no significant improvement in performance was revealed with right hemispace presentation of stimuli or left cue prompts combined with the right hemispace version. Ancillary predictions concerning correlations for the neglect measures and MFD scoring systems were confirmed. Results are interpreted in terms of increased attentional demands and task complexity. These results suggest that, despite the frequent clinical use of these manipulations in the cognitive assessment of this population, support for the efficacy of these procedures is lacking.

To date, no research exists examining criterion-related validity of alternate, computerized forms of the Category Test. The intent of this study was to address criterion-related validity of three full forms of the Category Test. In that, the goal was to examine equivalency of each version in their ability to differentiate brain-injured from non-brain-injured individuals. Forty-nine (N = 49) healthy adults and 45 (N = 45) brain-injured adults were tested using three versions of the Category Test, the BDI, and the WAIS-R NI. ANOVA indicated no significant differences between versions of the Category Test or an interaction between Category Test version and group membership on the total error score. MANOVA performed between versions of the Category Test and Subtest error scores indicated significant differences between versions on Subtest 3 and Subtest 6. Group membership (brain-injured v. non-brain-injured) produced a significant main effect on all subtests of the Category Test except Subtest 2. Several exploratory analyses were performed examining the relationship between neuropsychological impairment, group membership based on Category Test error scores, and the WAIS-R NI. Clinical applications, such as the use of serial testing to index neurorehabilitation gains, were discussed.

Traumatic Brain Injury (TBI) and its resulting pathophysiology have been extensively examined before. However, little is known in the area of pre-injury factors that influence vulnerability to and recovery from TBI. The current study examined the effects of pre-injury chronic nicotine exposure on Morris water maze performance, following TBI in adolescent rats. Fifteen days prior to lateral fluid percussion injury (FPI), adolescent rats (30 days old) were implanted with osmotic mini-pumps filled with nicotine (4.5mg/kg/day) or saline. Half the rats received lateral fluid percussion injury and half received sham injury. Animals were assessed for cognitive recovery in the Morris water maze on post-injury days (PID) 11 through 15. The MWM results indicated no significant differences between injured animals infused with chronic nicotine and injured animals infused with saline.

The overall goal of this research is to develop methods and algorithms to investigate the severity of Traumatic brain injury (TBI) and to estimate the intracranial pressure (ICP) level non-invasively. Brain x-ray computed tomography (CT) images and artificial intelligence methods are employed to estimate the level of ICP. Fully anisotropic complex wavelet transform features are proposed to extract directional textural features from brain images. Different feature selection and classification methods are tested to find the optimal feature vector and estimate the ICP using support vector regression. By using systematic feature extraction, selection and classification, promising results on ICP estimation are achieved. The results also indicate the reliability of the proposed algorithm. In the following, case-based finite element (FE) models are extracted from CT images using Matlab, Solidworks, and Ansys software tools. The ICP estimation obtained from image analysis is used as an input to the FE modeling to obtain stress/strain distribution over the tissue. Three in-plane modeling approaches are proposed to investigate the effect of ICP elevation on brain tissue stress/strain distribution. Moreover, the effect of intracranial bleeding on ICP elevation is studied in 2-D modeling. A mathematical relationship between the intracranial pressure and the maximum strain/stress over the brain tissue is obtained using linear regression method. In the following, a 3-D model is constructed using 3 slices of brain CT images. The effect of increased ICP on the tissue deformation is studied. The results show the proposed framework can accurately simulate the injury and provides an accurate ICP estimation non-invasively. The results from this study may be used as a base for developing a non-invasive procedure for evaluating ICP using FE methods.

Acquired Brain Injury (ABI) can result in significant and long lasting additional needs for children, their families and the professionals tasked with supporting them (Middleton, 2001b; Walker & Wicks, 2005). This paper reports the two parts of a small scale study, the aim of which was to illuminate the factors (areas of good practice, issues & challenges) involved in educating children after ABI. The first paper explores the views and experiences of children and young people with ABI and their parents. It identifies how children describe their experiences of school since injury, their parent’s experience of the injury and schooling thereafter, as well as what areas of need exist in terms of improvement in support for this group of children and young people. The second part explores the views and experiences of school based practitioners as well as professionals from a range of external agencies that work with children, young people, their families and schools. The main aims were to stimulate discussion of what roles school staff and external agency professionals have in supporting children with ABI, the ways in which they work together and with children, young people and families and what, if any, improvements were thought to be important. Together, both parts of this research seek to illuminate pertinent factors for those involved, in order to inform future practice for Educational Psychologists (EPs) and the professionals they work with in schools and external agencies.