Our brain, perhaps the most sophisticated and mysterious part of the human body, to some extent, determines who we are. However, it’s a vulnerable organ. When subjected to an impact, such as a traffic accident or sport, it may lead to traumatic brain injury (TBI) which can have devastating effects for those who suffer the injury. Despite lots of efforts have been put into primary injury prevention, the number of TBIs is still on an unacceptable high level in a global perspective. Brain edema is a major neurological complication of moderate and severe TBI, which consists of an abnormal accumulation of fluid within the brain parenchyma. Clinically, local and minor edema may be treated conservatively only by observation, where the treatment of choice usually follows evidence-based practice. In the first study, the gravitational force is suggested to have a significant impact on the pressure of the edema zone in the brain tissue. Thus, the objective of the study was to investigate the significance of head position on edema at the posterior part of the brain using a Finite Element (FE) model. The model revealed that water content (WC) increment at the edema zone remained nearly identical for both supine and prone positions. However, the interstitial fluid pressure (IFP) inside the edema zone decreased around 15% by having the head in a prone position compared with a supine position. The decrease of IFP inside the edema zone by changing patient position from supine to prone has the potential to alleviate the damage to axonal fibers of the central nervous system. These observations suggest that considering the patient’s head position during intensive care and at rehabilitation should be of importance to the treatment of edematous regions in TBI patients. In TBI patients with diffuse brain edema, for most severe cases with refractory intracranial hypertension, decompressive craniotomy (DC) is performed as an ultimate therapy. However, a complete consensus on its effectiveness has not been achieved due to the high levels of severe disability and persistent vegetative state found in the patients treated with DC. DC allows expansion of the swollen brain outside the skull, thereby having the potential in reducing the Intracranial Pressure (ICP). However, the treatment causes stretching of the axons and may contribute to the unfavorable outcome of the patients. The second study aimed at quantifying the stretching and WC in the brain tissue due to the neurosurgical intervention to provide more insight into the effects upon such a treatment. A nonlinear registration method was used to quantify the strain. Our analysis showed a substantial increase of the strain level in the brain tissue close to the treated side of DC compared to before the treatment. Also, the WC was related to specific gravity (SG), which in turn was related to the Hounsfield unit (HU) value in the Computerized Tomography (CT) images by a photoelectric correction according to the chemical composition of the brain tissue. The overall WC of brain tissue presented a significant increase after the treatment compared to the condition seen before the treatment. It is suggested that a quantitative model, which characterizes the stretching and WC of the brain tissue both before as well as after DC, may clarify some of the potential problems with such a treatment. Diffusion Weighted (DW) Imaging technology provides a noninvasive way to extract axonal fiber tracts in the brain. The aim of the third study, as an extension to the second study was to assess and quantify the axonal deformation (i.e. stretching and shearing)at both the pre- and post-craniotomy periods in order to provide more insight into the mechanical effects on the axonal fibers due to DC. Subarachnoid injection of artificial cerebrospinal fluid (CSF) into the CSF system is widely used in neurological practice to gain information on CSF dynamics. Mathematical models are important for a better understanding of the underlying mechanisms. Despite the critical importance of the parameters for accurate modeling, there is a substantial variation in the poroelastic constants used in the literature due to the difficulties in determining material properties of brain tissue. In the fourth study, we developed a Finite Element (FE) model including the whole brain-CSF-skull system to study the CSF dynamics during constant-rate infusion. We investigated the capacity of the current model to predict the steady state of the mean ICP. For transient analysis, rather than accurately fit the infusion curve to the experimental data, we placed more emphasis on studying the influences of each of the poroelastic parameters due to the aforementioned inconsistency in the poroelastic constants for brain tissue. It was found that the value of the specific storage term S_epsilon is the dominant factor that influences the infusion curve, and the drained Young’s modulus E was identified as the dominant parameter second to S_epsilon. Based on the simulated infusion curves from the FE model, Artificial Neural Network (ANN) was used to find an optimized parameter set that best fit the experimental curve. The infusion curves from both the FE simulations and using ANN confirmed the limitation of linear poroelasticity in modeling the transient constant-rate infusion. To summarize, the work done in this thesis is to introduce FE Modeling and imaging technologiesincluding CT, DW imaging, and image registration method as a complementarytechnique for clinical diagnosis and treatment of TBI patients. Hopefully, the result mayto some extent improve the understanding of these clinical problems and improve theirmedical treatments. / QC 20120201

Traumatic brain injury (TBI) is a major cause of death and disability. Intracranial secondary insults (e.g. intracranial haematoma, brain oedema) and systemic secondary insults (e.g. hypotension, hypoxaemia, hyperthermia) lead to secondary brain injury and affect outcome adversely. In order to minimise secondary insults and to improve outcome in TBI-patients, a secondary insult program and standardised neurointensive care (NIC) was implemented. The aim of this thesis was to describe patient outcome and to explore the occurrence and prognostic value of secondary insults after the implementation. Favourable outcome was achieved in 79% and 6% died of the 154 adult TBI patients treated in the NIC unit 1996-97. In an earlier patient series from the department, 48% made a favourable outcome and 31% died. Hence, the outcome seems to have improved when NIC was standardised and dedicated to avoiding secondary insults. Secondary insults counted manually from hourly recordings on surveillance charts did not hold any independent prognostic information. When utilising a computerised system, which enables minute-by-minute data collection, the proportion of monitoring time with systolic blood pressure > 160 mm Hg decreased the odds of favourable outcome independent of admission variables (odds ratio 0.66). Hyperthermia was related to unfavourable outcome. Hypertension was correlated to hyperthermia and may be a part of a hyperdynamic state aggravating brain oedema. Increased proportion of monitoring time with cerebral perfusion pressure (CPP) < 60 mm Hg increased the odds of favourable outcome (odds ratio 1.59) in patients treated according to an intracranial pressure (ICP)-oriented protocol (Uppsala). In patients given a CPP-oriented treatment (Edinburgh), CPP <60 mm Hg was coupled to an unfavourable outcome. It was shown that pressure passive patients seem to benefit from an ICP-oriented protocol and pressure active patients from a CPP-oriented protocol. The overall outcome would improve if patients were given a treatment fit for their condition.

Severe Traumatic Brain Injury (TBI) and aneurysmal Subarachnoid Hemorrhage (SAH) are severe cerebral emergencies. They are common reasons for extensive morbidity and mortality in young people and adults in the western world. This thesis, based on five clinical studies in patients with severe TBI (I-IV) and SAH (V), is concentrated on examination of pathophysiological developments and of evaluation of therapeutic approaches in order to improve outcome after cerebral emergency. The treatment for severe TBI patients at Umeå University Hospital, Sweden is an intracranial pressure (ICP)-targeted therapy according to “the Lund-concept”. This therapy is based on physiological principles for cerebral volume regulation, in order to preserve a normal cerebral microcirculation and a normal ICP. The main goal is to avoid development of secondary brain injuries, thus avoiding brain oedema and worsened microcirculation. Study I is evaluating retrospectively 41 children with severe TBI, from 1993 to 2002. The boundaries of the ICP-targeted protocol were obtained in 90%. Survival rate was 93%, and favourable outcome (Glasgow Outcome Scale, score 4+5) was 80%. Study II is retrospectively analysing fluid administration and fluid balance in 93 adult patients with severe TBI, from 1998 to 2001.The ICP-targeted therapy used, have defined fluid strategies. The total fluid balance was positive day one to three, and negative day four to ten. Colloids constituted 40-60% of total fluids given/day. Severe organ failure was evident for respiratory insufficiency and observed in 29%. Mortality within 28 days was 11%. Study III is a prospective, randomised, double-blind, placebo-controlled clinical trial in 48 patients with severe TBI. In order to improve microcirculation and prevent oedema formation, prostacyclin treatment was added to the ICP-targeted therapy. Prostacyclin is endogenously produced, by the vascular endothelium, and has the ability to decrease capillary permeability and vasodilate cerebral capillaries. Prostacyclin is an inhibitor of leukocyte adhesion and platelet aggregation. There was no significant difference between prostacyclin or placebo groups in clinical outcome or in cerebral microdialysis markers such as lactatepyruvate ratio and brain glucose levels. Study IV is part of the third trial and focus on the systemic release of pro-inflammatory mediators that are rapidly activated by trauma. The systemically released pro-inflammatory mediators, interleukin-6 and CRP were significantly decreased in the prostacyclin group versus the placebo group. Study V is a prospective pilot study which analyses asymmetric dimethylarginine (ADMA) concentrations in serum from SAH patients. Acute SAH patients have cerebral vascular, systemic circulatory and inflammatory complications. ADMA is a marker in vascular diseases which is correlated to endothelial dysfunction. ADMA concentrations in serum were significantly elevated seven days after the SAH compared to admission and were still elevated at the three months follow-up. Our results show overall low mortality and high favourable outcome compared to international reports on outcome in severe TBI patients. Prostacyclin administration does not improve cerebral metabolism or outcome but significantly decreases the levels of pro-inflammatory mediators. SAH seems to induce long-lasting elevations of ADMA in serum, which indicates persistent endothelial dysfunction. Endothelial dysfunction may influence outcome after severe cerebral emergencies.

Rehabilitation after brain injury is often a process which is spread over several years and runs through different phases. After sub acute in-patient rehabilitation a community based post-acute rehabilitation can follow. In this late phase after injury the rehabilitation focuses on reintegration into the community through a return to work and participation in other occupations in society. The overall aim of this dissertation was to study the long-term outcome of brain injury, with a special emphasis on the return to everyday domestic and productive occupations and the connection these have to life satisfaction as a whole. The aim was also to describe and understand the lived experience of the consequences of brain injury in these areas. This dissertation comprises four studies on different aspects of the long-term outcome of those who have had a brain injury. In a sample of 56 people, the value of occupational therapy assessments as predictors of an eventual return to work was investigated. In a longitudinal follow-up study, the life satisfaction of the participants (n 36) was reported and its correlation to a return to work was evaluated. Interviews were conducted (n 10) to explore the main characteristics of the meaning of work after brain injury in ten respondents. And, finally, in the fourth study, 157 people reported their participation in community activities. The extent of the correspondence between the level of participation and life satisfaction was calculated. The findings showed that occupational therapy assessments were useful in predicting a return to work in the late phase of the recovery after brain injury. A combination of assessments on the level of body function with assessments on activity level appeared to comprise the best predictive model. In two different studies the reported life satisfaction was found to be significantly lower than the level of life satisfaction in a sample of healthy Swedes for almost all domains. When comparing life satisfaction at two points in time with an interval of three years between them in the longitudinal study, no significant improvement was found. There was no difference reported by the participants for their overall life satisfaction regardless of whether they were back at work or in education, or not. On the other hand, participation in daily occupations in a wider perspective was found to have a positive impact on satisfaction with life as a whole. However, half or more than half of the participants claimed that their participation was restricted except for the items self-care and mobility, where a higher degree of participation was reported. The meaning of work after the brain injury had changed: Work had taken on a new place in life and the importance of work had decreased. In contrast, the social dimension of work had expanded in importance. After the brain injury, the perception of the participants’ own competence and work identity had changed and the respondents described their striving to return to normality. To conclude, brain injury has a lasting effect on a person’s life, even many years after the injury; consequently there is need for rehabilitation in this late phase. Life satisfaction, which is often used as an overriding goal for rehabilitation, did not improve over time. This finding raises the question of whether life satisfaction is too broad a concept and/or insufficiently sensitive to improvements. There is need for further research in this area to clarify the factors that have an impact on life satisfaction.

The controlled lowering of core body temperature to 32°C to 34°C is defined as therapeutic hypothermia (TH). Therapeutic hypothermia has been shown to improve neurological outcome and survival in unconscious patients successfully resuscitated after cardiac arrest. Brain temperature is important for cerebral protection therefore methods for primarily cooling the brain have also been explored. This thesis focuses on the likelihood that intranasal cooling can induce, maintain and control cerebral hypothermia. The method uses bilaterally introduced intranasal balloons circulated with cold saline. Selective brain cooling induced with this method was effectively accomplished in pigs with normal circulation while no major disturbances in systemic circulation or physiological variables were recorded. The temperature gradients between brain and body could be maintained for at least six hours. Intranasal balloon catheters were used for therapeutic hypothermia initiation and maintenance during and after successful resuscitation in pigs. Temperature reduction was also obtained by combined intranasal cooling and intravenous ice-cold fluids with possible additional benefits in terms of physiologic stability after cardiac arrest. Rewarming was possible via the intranasal balloons. In these studies brain temperature was recorded invasively by temperature probes inserted in the brain. The fast changes in pig’s brain temperature could also be tracked by a non-invasive method. High-spatial resolution magnetic resonance spectroscopic imaging (MRSI) without internal reference showed a good association with direct invasive temperature monitoring. In addition the mapping of temperature changes during brain cooling was also possible. In awake and unsedated volunteers subjected to intranasal cooling brain temperature changes were followed by two MR techniques. Brain cooling was shown by the previously calibrated high-spatial resolution MRSI and by the phase-mapping method. Intranasal cooling reduced body temperature slightly. The volunteers remained alert during cooling, the physiological parameters stable, and no shivering was reported.

Με τον όρο «Έκτοπη Οστεοποίηση» περιγράφεται ο σχηματισμός οστού σε σημεία που υπό φυσιολογικές συνθήκες δεν υφίσταται. Τα σημεία αυτά μπορεί να είναι μύες, τένοντες ή σύνδεσμοι και γενικότερα μεσεγχυματικού τύπου μαλακά μόρια, κυρίως γύρω από τις μεγαλύτερες αρθρώσεις. Η επίκτητη μορφή της νόσου, που είναι και η πιο κοινή, εμφανίζεται μετά από μυοσκελετικούς τραυματισμούς, κακώσεις του νωτιαίου μυελού και του κεντρικού νευρικού συστήματος γενικότερα, αλλά και σε περιπτώσεις σοβαρών εγκαυμάτων. Η παθοφυσιολογία της έκτοπης οστεοποίησης παραμένει άγνωστη, αυτό που γνωρίζουμε με βεβαιότητα είναι ότι για τον σχηματισμό της απαιτούνται τρείς βασικές προϋποθέσεις που είναι α) τα οστεοπρογονικά κύτταρα, β) οι κατάλληλοι επαγωγικοί παράγοντες και γ) το ευνοϊκό οστεοεπαγωγικό περιβάλλον. Στην παρούσα εργασία με την χρήση κυτταρομετρίας ροής, δοκιμασιών με ηλεκτροχημειοφωταύγεια, Elisa και ανοσοπροσδιορισμού με χρήση Cytometric Bead Array προσδιορίσαμε τις συγκεντρώσεις των total procollagen type 1 amino-terminal propeptide (TP1NP), osteoprotegerin (OPG), β-isomerized C-terminal telopeptides (β- Crosslaps), soluble receptor activator of nuclear factor kappa-B ligand (sRANKL), N-MID osteocalcin, S100 και των κυτταροκινών IL-2, IL-4, IL-6, IL-10, INF-γ και TNF-a στον ορό ασθενών και υγιών μαρτύρων. Επιπλέον, στο ολικό αίμα προσδιορίσαμε τον πληθυσμό των θετικών στην οστεοκαλσίνη κυττάρων. Όλα τα προς μελέτη μόρια είχαν άμεση ή έμμεση σχέση με την οστική ανακατασκευή και τις φλεγμονώδεις αντιδράσεις. Συνολικά μελετήθηκαν 55 ασθενείς από τους οποίους ελήφθησαν δείγματα καθόλη την διάρκεια νοσηλείας τους. Οι ασθενείς μελετήθηκαν με βάση το είδος του τραύματος, την εμφάνιση ή όχι έκτοπης οστεοποίησης και την έκβαση της κατάστασης τους. Επιπλέον, οι επιμέρους ομάδες ασθενών μελετήθηκαν συναρτήσει του χρόνου. Τα αποτελέσματα μας έδειξαν ότι στο σύνολο των ασθενών παρατηρήθηκαν στατιστικά μειωμένα επίπεδα β- crosslaps, N-MID osteocalcin, sRANKL και S100 συγκριτικά με τους υγιείς μάρτυρες. Αντίθετα, τα επίπεδα των TP1NP, των θετικών στην οστεοκαλσίνη κυττάρων, της OPG, της INF-γ και της IL-6 ήταν στατιστικά σημαντικά αυξημένα. Επιπλέον, στατιστικά σημαντικά αυξημένα παρατηρήθηκαν τα επίπεδα του S100 στους ασθενείς που είχαν υποστεί κρανιοεγκεφαλικές κακώσεις κατά το πρώτο εικοσιτετράωρο μετά την επαγωγή της κάκωσης. Στατιστικά σημαντικά αυξημένο επίσης παρατηρήθηκε και στην ομάδα των ασθενών με κακή έκβαση συγκριτικά με τους υγιείς δότες. Στην ίδια ομάδα ασθενών παρατηρήθηκε μια γενικευμένη αύξηση των επιπέδων των κυτταροκινών που φαίνεται να σχετίζεται άμεσα με την κακή έκβαση της κατάστασης τους. Πιο συγκεκριμένα η αύξηση αυτή ήταν στατιστικώς σημαντική για τις IL-4, INF-γ και TNF-α. / Heterotopic ossification (HO) is the presence of bone in soft tissue where normally does not exist. The acquired form, which is also the most common, develops after musculoskeletal trauma, spinal cord injury or central nervous system injury and severe burns. Pathophysiology of OH still remains unclear, what we know is that the formation of ectopic bone requires three entities which are a) osteogenic precursor cells, b) inducing agents and c) an appropriate environment. In the present study using either flow cytometry, Elisa, electrochemiluminescence immunoassays or cytometric bead array assays we determined the concentrations of the osteoblast progenitors: osteocalcin positive cells in peripheral blood and the serum concentrations of total procollagen type 1 amino-terminal propeptide (TP1NP), osteoprotegerin (OPG), β-isomerized C-terminal telopeptides (β- Crosslaps), soluble receptor activator of nuclear factor kappa-B ligand (sRANKL), N-MID osteocalcin, S100 and the cytokines IL-2, IL-4, IL-6, IL-10, INF-γ and TNF-a. All measured molecules participate directly or indirectly in bone formation and metabolism and in inflammation. Our 55 patients were divided and studied in 3 different ways, regarding the kind of their injury, their outcome and the formation of HO. They were also monitored in course of time. Among our most interesting results is that patients had significantly lower levels of β- crosslaps, N-MID osteocalcin, sRANKL and S100 compared to healthy donors. On the other hand, levels of TP1NP, osteocalcin positive cells, OPG, INF-γ and IL-6 were significantly higher. S100 is significantly increased during the first 24 hours in patients who have sustained traumatic brain injury. In addition, S100 was significantly increased in patients with poor outcome compared to healthy donors. Furthermore, patients with poor outcome seem to develop a cytokine storm which is of great importance for their outcome. All measured cytokine levels were increased compared to patients with good outcome. Especially for IL-4, INF-γ, TNF-α this increase was statistically significant.

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The number of informal carers in the UK is rising, yet the dynamics of care within informal care relationships remain poorly understood. The present research examined adaptation of informal care relationships affected by Acquired Brain Injury. The research addresses four pairs of questions: (1a) Are there any disagreements and/or misunderstandings between carers and people with Acquired Brain Injury (PwABI) regarding carer identity? (1b) How can the pattern of divergences be explained? (2a) Are there any disagreements and/or misunderstandings between carers and PwABI regarding PwABI identity? (2b) How can the pattern of divergences be explained? (3a) What strategies do carers and PwABI use in collaboration on a joint task? (3b) Is the type of input provided by carers on the joint task comparable to scaffolding as described in the child development literature? (4a) What happens when carers and PwABI collaborate to fill in the Disability Living Allowance (DLA) claim form? (4b) Why do carers see more disability than PwABI when filling in the DLA form? Four mixed-method data sets were used to answer these questions: (1) numerical ratings given by PwABI and carers to map out convergences and divergences (2) videos of discussions between participants and researcher during rating tasks (3) videos of carers and PwABI engaging in a joint task - planning inviting a friend or relative round for a meal and (4) videos of carers and PwABI filling in part of the DLA claim form. All data was collected from the same 28 PwABI/carer dyads who were two or more years post injury. Chapter 4 addresses questions 1a and 1b. Carers’ and PwABIs’ perspective ratings revealed a number of disagreements regarding carer identity. Carers perceived themselves negatively compared to their partners’ view of them. Regarding question 1b, carers feel negatively about themselves due to difficulties in the transition to the role of ‘carer’. They experience a lack of recognition for this caring role as a result of concealing the burden of care. Carers require more long term support from health services to help them achieve recognition for their role, such as facilitating attendance at support groups. Chapter 5 addresses questions 2a and 2b. Carers’ and PwABIs’ perspective ratings revealed only one disagreement and corresponding misunderstanding regarding PwABI identity. Regarding question 2b, alignment was found between the perspectives of carers and PwABI regarding PwABI due to the relational rating method used. It is carer identity which is the source of most divergences of perspective, not PwABI identity as commonly assumed. Using a relational rating method shows promise as a tool to explore perspectives as it treats all viewpoints as equal and avoids pathologising the perspective of PwABI. Chapter 6 addresses questions 3a and 3b. Analysis of strategies shows that completing a joint task is a collaborative process. Carers direct the background of the task but PwABI are in charge of the foreground, making task decisions. However, carers dominate the process and control where and how PwABI contribute. Regarding question 3b, the interaction meets the criteria for scaffolding in the strategies chosen and the flexibility of collaboration. However, removal of supports is often an unrealistic goal, leading to frustration in carers. Examination of processes of collaboration has elucidated the strategies used by carers and PwABI and can enhance theoretical discussion of the applicability of the scaffolding metaphor for a cognitively impaired adult sample. Chapter 7 address questions 4a and 4b. Disagreements were frequent when completing the DLA form. Contestations were almost exclusively in the direction of carers seeing greater disability than PwABI. Regarding question 4b, carers see greater disability due to the communication required to complete the form. Dyads are forced to confront disability, a pattern of interaction they avoid in everyday life. Carers marginalise PwABI point of view and position themselves as ‘expert’ on the PwABI. Differences in frames of reference regarding audience, aim and scope lead carers to maximise the disability and PwABI to minimise this. The impact of completing complex forms on relationships and identity needs to be considered during development of disability benefit assessment methods. A relational approach which studies both halves of informal care partnerships simultaneously allows us to go beyond outcomes of ABI and affords a greater understanding of processes of adaptation.

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