Thesis (Ph. D.)--UCLA, 2009. / Vita. Includes bibliographical references.

Thesis (Ph.D.) - University of Queensland, 2004. / Includes bibliography.

Thesis (M.S.)--University of Florida, 2004. / Typescript. Title from title page of source document. Document formatted into pages; contains 56 pages. Includes Vita. Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 58-62).

This study examines the validity of using a combination of two psychometric measures, an emotional adjustment measure, and functional assessment measures to predict vocational outcome in a traumatically brain injured population. Patients included 33 males and 11 females, with an average age of 32.3 years, and a stable work history over the past three years prior to injury. All had sustained a traumatic brain injury in the 12 months prior to initial testing, with a mean of 3.8 months since injury. Levels of severity of injury included 24 patients with severe injury, 12 patients with moderate injury, and 8 patients with mild injury. Patients completed the Logical Memory subtest (LM) of the Wechsler Memory Scale-Revised, Paced Auditory Serial Addition Test (PASAT), Beck Depression Inventory (BDI), and Personal Capacities Questionnaire (PCQ). A clinician working closely with the patient also completed the Functional Assessment Inventory (FAI) and the Behavior Checklist (BC) at the time of initial testing. Follow-up testing on available patients (n=16) was completed approximately six months after initial testing. Comparison of the functional assessment measures demonstrated that patients exhibited a decreased awareness of functional limitations relative to clinician's ratings, but identified an increased number of personal strengths. The present study demonstrates the first comparison of FAI and PCQ ratings in a TBI population, as well as the first available field research using the PCQ. Results also indicated that the only significant predictor on earned income after six months was the overall functional limitations score on the PCQ. The only significant difference in patients' test performance at six months with scores at initial testing was seen on the PASAT, which suggested that patients had a significant improvement in their speed of information processing after six months. In addition, comparison of patients from Canadian and American rehabilitation agencies, respectively, revealed no significant differences between patients at either initial testing or at follow-up. / Graduate

This project explored two main areas: the assessment of apraxia and the intervention effectiveness in rehabilitation of the apraxic condition. This was achieved through a group study and a series of single case designs. Three experimental groups were used to investigate clinical tests and the kinematics ofmovement~ apraxic (n=17) and non-apraxic (n=13) left hemisphere damaged patients, and normal control subjects (n=ll). Using computergraphic techniques, the data provided evidence of disruption to the temporalspatial aspects of movement in apraxic people, which was not related to modality of testing, though some normal kinematic profiles were found within the apraxic group. Clinical assessments used to identify apraxia showed no relationship one with another which suggested each was identifying different aspects, or sub-types of a heterogeneous condition. Some tests were found to have low internal consistency, though inter-rater reliability through the observer-judgment process was high. A test devised for identifying agnosia was shown to relate to possible cognitive-perceptual processes or intact vision-to-action routes in the apraxic movement output. Dissociations found between clinical assessments for apraxia and kinematics of movement were explained in relation to different compensatory movement strategies employed by the apraxic patients, and/or as evidence for possible 'sub-types' of the apraxic condition. Analysis also suggested that different task demands might determine compensatory movement strategies and produce altered movement kinematics. This group study was followed by a series of single cases, two of which charted the 'natural history' process in recovery of apraxia using task performance and kinematic analysis as outcome measures. Evidence for spontaneous recovery over a six week period was shown in one case. Four single case ABA design investigations were then carried out on individuals with ideomotor and ideational apraxia to determine the effectiveness of intervention strategies. Specific sensory stimulation protocols were evaluated with no convincing evidence for effectiveness of the intervention, though both natural recovery improvements and learning effects were seen in the outcome measures. Variability of performance was a feature of all cases studied and could be considered a feature of the apraxic condition. Task break-down strategies were also evaluated in functional activities and demonstrated some effectiveness in a case of ideomotor apraxia, though a case with an ideational component indicated a more intractable condition. The strategy was not seen to generalise to other unpracticed tasks. In conclusion, the associations and dissociations found between movement kinematics and the clinical assessment tests for apraxia suggested the presence of 'sub-types' within the blanket diagnosis of the condition. Identification of such sub-types might be facilitated by the development of the agnosia test newly devised for this project. Finally, research into intervention effectiveness in apraxia calls for further investigation to determine what procedures might be used with different sub-types of the condition.

Normal pressure hydrocephalus (NPH) is characterised by a build-up of cerebrospinal fluid (CSF) in the brain despite apparently normal CSF pressure at lumbar puncture. In addition to movement and urinary symptoms, patients commonly display cognitive decline and apathy. NPH is recognised as an important cause of cognitive decline as it is thought be reversible with surgical CSF diversion (e.g. shunt surgery). However, this remains controversial and the neuropsychology of NPH is relatively poorly understood. Further, despite being the most commonly reported neuropsychiatric symptom in NPH, the significance of the symptom of apathy has not yet been elucidated. This thesis aims to expand on the neuropsychological and neuropsychiatric research in NPH, with the main objectives being to investigate neuropsychological outcome, and the significance of the symptom of apathy in NPH. In order to investigate neuropsychological outcome following shunt surgery in NPH, a systematic review and meta-analysis was conducted (Chapter 2). The findings from studies which used a battery of neuropsychological tests to assess cognitive outcome in NPH were combined. Meta-analyses were conducted on pre-operative and difference scores for the most commonly used neuropsychological tests. These were seven tests which spanned global cognitive function, learning and memory, executive function and psychomotor speed. Results for all tests were significant in the direction of improvement. However, the significance of the results for two measures of executive function were deemed not to be robust. This is discussed in line with previous research which suggests that executive function may be less likely to improve following shunt surgery than other neuropsychological domains. Next, the thesis focuses on the symptom of apathy. Chapter 3 investigated whether apathy in NPH relates to cognitive outcome and to a measure of ventricular enlargement. A reduction in apathetic symptoms following treatment was associated with better performance in a measure of global cognitive function. Further, larger ventricles (which may indicate greater disease severity/ brain damage) was associated with more severe apathy. A structural MRI study was then conducted to expand on these findings and to define brain structural correlates of apathy in NPH (Chapter 4). Results from this study suggested a potential role of the caudate nuclei in apathetic symptoms in NPH. Finally, consideration is given to the assessment of apathy in NPH. Since apathy is rarely investigated in patients with NPH it is unclear which assessment method is most appropriate for this patient group. Chapter 5 presents findings from a feasibility study of a novel reward learning task to determine whether it might be useful as an objective measure of motivation and apathy in NPH.

The β1-adrenoceptor (β1-AR) is an important regulator of cardiac function. Chronic stimulation and subsequent downregulation of cardiac β1-ARs have been implicated in heart failure. Recently, it has been demonstrated that antibodies which target the second extracellular loop (ECL2) of the human β1-AR play a role in the pathogenesis of some forms of cardiomyopathy. Heptares Therapeutics Ltd. developed a murine monoclonal antibody (mAb3) raised against the thermostabilised turkey β1-adrenoceptor which had ECL2 as the epitope. MAb3 was previously characterised in CHO cells transiently expressing the turkey β1-AR. This thesis characterises the pharmacology of mAb3 at the human and turkey β1-AR in stable CHO cell lines. Initial studies confirmed mAb3 was able to bind to the ECL2 of the turkey β1-AR and allow for the direct visualisation of these receptors expressed in whole CHO cells. MAb3 was specific for the turkey β1-AR with an affinity circa 20-30nM. The epitope of mAb3 represented an allosteric binding site on the turkey β1-AR, which was confirmed with whole cell radioligand binding. Applying a model of functional allosterism, mAb3 behaved as a negative allosteric modulator of an orthosteric ligand in functional assays in CHO cells stably expressing the turkey β1-AR, whilst having no effect on the human β1-AR. MAb3 did not affect the secondary binding site agonistic responses mediated by the partial agonist CGP 12177. The recently developed NanoBRET technique was applied here to monitor ligand binding at the human β1-AR. Specific binding of three fluorescent ligands could be measured with this technique. These ligands were then used as probes to accurately calculate the affinities of a panel of unlabelled β-adrenoceptor ligands. Affinity values obtained appeared to show probe dependence, however when the incubation time was increased the differences in affinities disappeared. This highlighted the importance of ensuring equilibrium was achieved before analyses of probe dependence could be made.

Experience of the bodily self is dependent upon the integration of current sensory signals with existing knowledge and prior expectations about the body. As such, the way in which the self is perceived is not a direct reflection of the body’s actual state, but rather an interpretation of available sensory information. The phenomena of “medically unexplained symptoms” provide an illustration of this, whereby individuals experience subjectively real somatic symptoms despite the absence of any organic cause. The work in this thesis aimed to investigate how individuals experiencing somatic symptoms process multisensory information about the body and, more specifically, set out to test the hypothesis that symptom reporting is associated with a general tendency to over-weight top-down information during the process of body representation. The role of visual information in shaping bodily perception was explored by using visual manipulations that distorted the appearance of the body, introducing a discrepancy between sensory information and top-down knowledge about the body. The findings show that visual information can have a significant effect on the way in which the body is perceived, and also demonstrate that perception of the self arises from a dynamic interaction between top-down and bottom-up inputs (Chapters 2 and 3). Contrary to hypotheses, the results do not support suggestions that somatic symptom experience is characterised by disturbances in body representation; individuals who report a higher number of somatic symptoms were found to process multisensory information about the body in a comparable way to those who reported few symptoms, demonstrating that somatic symptom experience is not associated with abnormal processing of visual, spatial and temporal sensory information about the body (Chapters 4 and 5). Furthermore, there is no evidence to suggest that high symptom reporters rely more on top-down information during the process of body representation, even in the presence of strong contextual cues (Chapters 5 and 6). The final study also observed no relationship between somatic symptom reporting and interoceptive accuracy, indicating that high symptom reporters perceive and integrate both exteroceptive and interoceptive sensory information in a typical fashion (Chapter 6). Overall, this work uses experimental methods to explore a number of theoretical concepts proposed as relevant for unexplained symptoms, concluding that somatic symptom experience amongst the general population is not characterised by abnormal multisensory integration or disrupted body representation.

Specific locations within the brain contain neurons which respond, by firing action potentials (spikes), when a sound is played in the ear of a person or animal. The number and timing of these spikes encodes information about the sound; this code is the basis for us perceiving and understanding the acoustic world around us. To understand how the brain processes sound, we must understand this code. The difficulty then lies in evaluating the unknown neural code. This thesis applies Machine Learning to evaluate auditory coding of dynamic sounds by spike trains, with datasets of varying complexity. In the first part, a battery of Machine Learning (ML) algorithms are used to evaluate modulation frequency coding from the neural response to amplitude-modulated sinusoids in cat Cochlear Nucleus spike train data. It is found on this recognition task that, whilst absolute performance levels depend on the types of algorithms, their performance relative to each other is the same on different types of neurons. Thus a single powerful classification algorithm is sufficient for evaluating neural codes. Similarly, different performance measures are useful in understanding differences between ML algorithms, but they shed little light on different neural coding strategies. In contrast, the features used for classification are crucial; e.g. Vector Strength does not provide an accurate measure of the information contained in spike timing. Overall, different types of neurons do not encode the same amount of amplitude-modulation information. This emphasises the value of using powerful Machine Learning methods applied to raw spike timing information. In the second part, a more ecological and heterogeneous set of sounds — speech — is used. The application of Hidden Markov Model based Automatic Speech Recognition (ASR) is tested within the constraints of an electrophysiological experiment. The findings suggest that a continuous digit recognition task is amenable to a physiology experiment: using only 10 minutes of simulated recording to train statistical models of phonemes, an accuracy of 70% could be achieved. This result jumps to about 85% when using 200 minutes worth of simulated data. Using a digit recognition framework is sufficient to examine the influence on the performance of different aspects of the size and nature of a neural population and the role of spike timing. Previous results suggest, however, that this accuracy would be reduced if experimental Inferior Colliculus data were used instead of a guinea-pig cochlear model. On the other hand, a fully-fledged continuous ASR task on a large vocabulary with many speakers may result in insufficient phoneme accuracy (∼40%) to base an auditory coding-related investigation on. Overall this suggests that complex ML algorithms such as ASR can nevertheless be practically used to assess neural coding of speech, with careful selection of features.