This thesis presents a method for the segmentation of dual-channel structural magnetic resonance imaging (MRI) volumes of the human brain into four tissue classes. The state-of-the-art FSL FAST segmentation software (Zhang et al., 2001) is in widespread clinical use, and so it is considered a benchmark. A significant proportion of FAST’s errors has been shown to be localised to cortical sulci and blood vessels; this issue has driven the developments in this thesis, rather than any particular clinical demand. The original theme lies in preserving and even restoring these thin structures, poorly resolved in typical clinical MRI. Bright plate-shaped sulci and dark tubular vessels are best contrasted from the other tissues using the T2- and PD-weighted data, respectively. A contrasting tube detector algorithm (based on Frangi et al., 1998) was adapted to detect both structures, with smoothing (based on Westin and Knutsson, 2006) of an intermediate tensor representation to ensure smoothness and fuller coverage of the maps. The segmentation strategy required the MRI volumes to be upscaled to an artificial high resolution where a small partial volume label set would be valid and the segmentation process would be simplified. A resolution enhancement process (based on Salvado et al., 2006) was significantly modified to smooth homogeneous regions and sharpen their boundaries in dual-channel data. In addition, it was able to preserve the mapped thin structures’ intensities or restore them to pure tissue values. Finally, the segmentation phase employed a relaxation-based labelling optimisation process (based on Li et al., 1997) to improve accuracy, rather than more efficient greedy methods which are typically used. The thin structure location prior maps and the resolution-enhanced data also helped improve the labelling accuracy, particularly around sulci and vessels. Testing was performed on the aged LBC1936 clinical dataset and on younger brain volumes acquired at the SHEFC Brain Imaging Centre (Western General Hospital, Edinburgh, UK), as well as the BrainWeb phantom. Overall, the proposed methods rivalled and often improved segmentation accuracy compared to FAST, where the ground truth was produced by a radiologist using software designed for this project. The performance in pathological and atrophied brain volumes, and the differences with the original segmentation algorithm on which it was based (van Leemput et al., 2003), were also examined. Among the suggestions for future development include a soft labelling consensus formation framework to mitigate rater bias in the ground truth, and contour-based models of the brain parenchyma to provide additional structural constraints.

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Based on ten experiments, this thesis examines representational neglect in brain damaged patients and in matched controls.  The patients sometimes show a specific deficit in visual imaging:  neglected one half of their mental representations.  Although several studies addressed the issue of visuo-perceptual neglect, the representational defect is underinvestigated.  Only a few standardized tests are available for its detention and assessment, and therefore rarely it is diagnosed in clinical practise or investigated in experimental work.  In this thesis some new tests to investigate representational neglect are proposed.  Moreover, representational neglect is evaluated in different sensory modalities (visual, tactile as well as within the personal domain) to address the issue of supramodality or plurimodality of this deficit.

Electrical eddy currents can be induced inside biological tissue by time-varying magnetic fields according to Faraday's law of induction. These eddy currents are responsible for biological effects such as visual sensations in eyes called magnetophosphenes and they accelerate the healing process of fractured bones in magnetotherapy operation. Induced eddy currents also cause neuromuscular stimulation of cardiac muscle, shown as a disturbance in the electrocardiogram and respiratory disturbance shown as a brief period of apnoea (stopped breathing) and muscle contraction in the forearm and finger. Brain cortex also can be stimulated by pulsed magnetic fields. A transient decrease in blood flow in the human skin is seen as a result of exposing the skin to pulsed magnetic fields. To study the effects of time-varying magnetic field, a method is needed to assess and measure induced current densities. Many attempts have been made to find such a method, both theoretically and practically. A theoretical model with homogenous and isotropic concentric loops of tissue was suggested but biological tissues are neither homogenous nor isotropic. A Hall effect method using a slab of semiconductor was suggested for measurement of current densities inside tissues, but this method ignored disturbances in the current pathways inside the tissue as a result of differences in impedances between the semiconductor and the tissue. A cube substitution method using platinized conductive faces implanted in the tissue does not consider problems of alignment of the probes with the direction of isopotential lines or electrode-electrolyte impedance. Also, such electrodes measure only dc current. In a method using a three dimensional electrode to provide three-dimensional information, the author did not give evidence that these electrodes have a zero field distortion, and also did not give information about measurements made using his electrodes. None of the above methods provide a solid approach to the problems of measuring induced current densities. This thesis attempts to present a method of measuring induced current density. The method is capable of measuring both the magnitude and direction of induced current densities. It uses five point electrodes, four of them applied inside the tissue while the fifth one is just in electrical contact with the tissue. The method consists of a probe configuration system, an open-loop operational amplifier and a balanced semi-floating current driver. Leakage current, which goes to the ground and causes error, can be adjusted to be very low (about 0.01% of the total output current). A pair of Helmoltz coils was employed to provide a system for producing time-varying magnetic field. The core of the coil pair was shielded and grounded by a cut metal shield, to avoid any interference from time-varying electric field. The shield was also used as a metal incubator to keep biological samples at body temperature. The heat to the shield was supplied by a unit consisting of four power transistors, and a circuit of sensing, and controlling components. The method used in this study was tested by making measurements of eddy current densities induced in physiological saline solution as a model of a biological conducting fluid. The measurements were represented by arrows, each representing a single measurement, with the length of the arrow representing the magnitude of current density and the direction representing the direction of the induced current. Because electrically induced eddy currents are dependent on electric charge density available inside tissue, and therefore dependent on tissue electrical conductivity, this thesis presents a direct and simple method for measuring complex tissue electrical conductivity. The method uses the same five-electrode system and shares the same point electrode configurations and balanced semi-floating current driver as used for eddy current measurements. The method measures both real and imaginary components of tissue complex conductivity. Both systems are gathered into one box and their functions are separated by four toggle switches. Measurements of electrical induced current densities and complex electrical conductivities for body fluids and tissues have been carried out on saline solutions with different ionic concentrations, expired human whole blood, expired human plasma, human cerebrospinal fluid (CSF) and human urine. Solid tissue such as bovine cardiac muscle and liver were also examined. Current-to-field ratios were obtained for experiments in both fluid and tissues.

This work describes 5 groups of tumours seen in routine neuropathological practice in Southampton between 1980 and 1986. The clinical and light microscopic findings in a total of 44 tumours are described. A panel of monoclonal and polyclonal antibodies was used in immunohistochemical studies on each group, and this made important contributions to the diagnosis and characterisation of these tumours. Six primary central nervous system lymphomas were shown to be 5 follicle centre cell lymphomas (Kiel-classification) and 1 T-cell lymphoma. 15 lymphomas causing spinal cord compression were typed as 11 follicle centre cell lymphomas, 3 T-cell lymphomas and 1 lymphoblastic lymphoma. T-cell lymphomas appear to be more likely to be localised in the spine and to have a better prognosis. In all these tumours admixed reactive cell populations were also identified immunohistochemically. Ten primitive neuroectodermal tumours of the cerebrum were examined and immunohistochemistry assisted in their distinction from lymphoma and metastatic carcinoma. It also showed evidence of differentiation in apparently poorly differentiated parts of the tumours. Immunohistochemical studies facilitated the distinction of pleomorphic xanthoastrocytoma from a monstrocellular astrocytoma and a meningeal malignant fibrous histiocytoma. The recognition of this first entity has important prognostic implications. In 10 cerebellar haemangioblastomas a panel of antibodies was used to investigate the histogenesis of the stromal cell component of these tumours. Endothelial and stromal cells were found to be antigenically distinct and neurone specific enolase activity was found in the latter. The implications of this finding are discussed. The studies confirm the important and increasing role played by immunohistochemistry in our understanding of central nervous system neoplasia.

Computerized cognitive retraining is a technique for remediation of the cognitive and behavioral changes which follow a traumatic brain injury. The technique utilizes specifically developed computer software which builds on the basic foundations of intellectual functioning. While the injured patient is the target of treatment, the method appeared to have an impact on the patient's family as well. Families of patients who participated in computerized cognitive retraining initially appeared to have fewer difficulties with anxiety, depression, and family problems. They also appeared to be more involved in the patient's treatment than were similar families who had not had this experience.The experiment evaluated the secondary psychological effects of computerized cognitive retraining on the brain injured patient's primary caretaker in the family. The dependent variables studied were perception of family involvement in patient treatment, anxiety, depression and perception of family problems.Subjects were recruited from the outpatient case load of the Psychology Department of Fort Sanders Regional Medical Center in Knoxville, Tennessee and from a local support group for families of patients who have experienced a traumatic brain injury. The injured patients and family members participated in the retraining technique. A total of seventeen patient/family member pairs participated in the study.Subjects participated in either the experimental or control treatments. The experimental group underwent five sessions of approximately one hour in length. The patient and family member worked together during the course of the retraining. Brief counseling followed each session. The treatment group used an Atari 800 computer and Bracy's "Foundations" cognitive retraining software package ( Psychological Software Services, Indianapolis, Indiana). The control group was a waiting list, minimum contact group, whose participation was limited to completion of the pre and posttest materials.Family members in both groups completed pre and posttesting packages. These included: a demographic questionnaire, the "Problem Solving Inventory" (Heppner, 1982a, 1982b), the "State/Trait Anxiety Inventory" (Speilberger, 1983), the "Beck Depression Inventory" (Beck, 1961), and the "Scale of Marriage Problems" (Swenson & Fiore, 1982).The experiment utilized Kerlinger's pretest-posttest control group design (Kerlinger, 1973). Patient/family pairs were randomly selected from the available subject pool. Control or experimental treatment groupings were assigned by stratified random sampling. Data were analyzed by the use of two way analysis of variance with repeated measures on one factor. Throughout the analysis, a level of R < .05 was required to infer statistical significance.The results of this experiment did not support the effectiveness of computerized cognitive retraining as a specific intervention method for the families of brain injured individuals. The findings revealed that there were no statistically significant differences between the control and treatment groups on measures of perception of family involvement, depression, or perception of family problems. The treatment group experienced a statistically significant increase in state anxiety following the experimental treatment. The validity, generalizability and implications for these findings were discussed in light of prior research.Recommendations for further research in the area of family response to computerized cognitive retraining include replication of the study with greater numbers of subjects and more sophisticated evaluation and treatment methodology. It is also suggested that future research address the patient's cognitive level, the utilization of varied retraining protocols specific to the patient's level of function, and premorbid psychosocial factors which may influence the process of cognitive remediation.

Boredom is a common human experience, yet little is known about its underlying neural mechanisms. This thesis first set out to investigate the construct of boredom and more closely examined its relationship to phenomenologically similar mood states of depression, apathy and anhedonia. Next, deficits in sustained attention, and novelty seeking were examined in patients with traumatic brain injury (TBI), who are characterized by atypically high levels of boredom. Study 1 established that although related to varying degrees to apathy, anhedonia, and depression, boredom is indeed a distinct emotional experience. Furthermore, two boredom proneness subtypes - agitated and apathetic - were identified which varied in their relationships to depression. The relationship between boredom and depression was found to be high only in the agitated boredom prone subtype, which is characterised by a high degree of motivation to engage in meaningful, stimulating activities despite the fact that all attempts to do so fail to satisfy. In Study 2, the relationship between boredom proneness and depression was found to be greater in TBI patients than in healthy controls. Using a behavioral measure of sustained attention (SART; Robertson et al., 1997), Study 3 demonstrated a relationship between boredom proneness and sustained attention in healthy controls, such that RTs were faster and commission errors more prevalent in the agitated boredom prone subtype. No relationship between boredom proneness and sustained attention was found in TBI patients. So while attention and boredom show a clear relationship in the healthy brain, this relationship may be disrupted in TBI patients. Finally, Study 4 demonstrated an association between agitated boredom proneness and a preference for novel stimuli across participant groups. In addition, patients had a poorer ability to discriminate between similar and dissimilar stimuli than controls, which was more evident in the agitated boredom prone group. It may be the case then that agitated boredom prone individuals fail to satisfy their desire to engage in stimulating activities in part because they fail to accurately identify when something is indeed novel. Taken together, these results highlight important distinctions between apathetic and agitated boredom proneness, and the way in which these subtypes relate to depression, attention, and novelty seeking, in brain injured patients and healthy controls. More work is needed to determine the role played by boredom in TBI, particularly as this evolves from acute to chronic stages of the illness. Importantly, identifying boredom as a key element in depressive mood disorders, attention deficits (e.g., attention deficit hyperactivity disorder), and novelty seeking behaviour, facilitates the design and implementation of appropriate intervention strategies. For example, it will become increasingly important to deal with boredom as a significant component of depression. Thus, the work presented here represents a novel and important contribution to the study of boredom in that it brings the field one step closer to understanding and treating the experience. Further investigation with greater numbers of patients is necessary to fully explicate the relationship between boredom and depression, attention, and novelty seeking in TBI.

Brain injuries (BI) are the leading cause of death and disability among people under the age of 45 (Ontario Brain Injury Association, 2004). With improved survival rates, more individuals each year return to the community with impairments and disabilities caused by their injury (Smith, Magill–Evans, and Brintnell, 1998). Adjusting to these impairments may affect the individual’s subjective well being; therefore, attention to community reintegration by researchers, policy developers, and health care providers is important. Using qualitative research methods and systems theory as the theoretical framework, the purpose of the study was to examine community reintegration from the perspectives of three key groups: individuals with BI, community based agencies, and primary care physicians regarding the meaning attributed to “successful reintegration”, as well as the key characteristics and barriers experienced during reintegration. “Successful” reintegration appears to be an individually derived concept. Participants consistently identified the need for information about the process of community reintegration, and resources available both during rehabilitation and after discharge from the hospital as being both a key aspect of community reintegration, as well as a barrier experienced during the return to community.

EGFR (Epidermal Growth Factor Receptor) is a protein that is ubiquitous in the human body. Aberrant activity of EGFR or its isoforms is implicated in a number of cancers, notably brain cancer. An isoform of EGFR, EGFRvIII (EGFR variant III), is particularly relevant to brain cancer since it is only naturally found in brain tumour tissue. However, the presence and activity of EGFRvIII is not well characterized. I hypothesize that the different levels of EGFRvIII expression and its expression relative to wild type EGFR in human brain tumour tissue can be used to diagnose the different stages and progression of disease in the glioblastoma multiforme (GM) type of brain cancer. The work presented in this thesis is an attempt to develop a method for the accurate and absolute quantitation of EGFRvIII from brain tumour tissue. Using iMALDI (immunoMALDI), which combines the high-specificity of MALDI mass spectrometry with antibody immunoaffinity enrichment, I have optimized and developed a highthroughput technique for sensitive, specific and quantitative detection and differentiation of EGFR and EGFRvIII. I have also demonstrated a proof-of-concept by applying this assay to the isolation and detection of these proteins from brain tumour tissue. / Graduate