The placebo effect represents a fascinating example of how cognition can influence the physiology of the brain and body. The expectation of therapeutic benefit elicited by a placebo given in the guise of active medication has been proposed to be a form of reward expectation, and is associated with activation of brain reward circuitry. Prominent placebo effects occur in Parkinson’s disease (PD), where the expectation of symptom improvement stimulates dopamine release in the striatum. In the work described in this dissertation, positron emission tomography with [¹¹C] raclopride was used to investigate the relationship between the strength of expectation of benefit and the degree of dopamine release in PD, and how this relationship corresponds to current models of dopamine function in reward. Chapter 3 describes a pilot study conducted in patients who had undergone subthalamic nucleus deep-brain stimulation (STN-DBS) in which we examined how awareness of stimulator status (ON or OFF) affected synaptic dopamine levels compared to when subjects were blind. No difference was detected between conditions; however, it proved to be difficult to maintain blinding due to the profound effects of STN-DBS. Chapter 4 describes the development of the methodology for the analysis of high-resolution PET data, in which we utilized the combined efforts of neuroscience and imaging physics to optimize the analysis of [¹¹C] raclopride PET data. In Chapter 5, I describe the use of verbal instructions to manipulate patients’ expectations in order to investigate how the likelihood of receiving levodopa influenced dopamine release when the patients were in fact given placebo. Placebo-induced dopamine release was differentially modulated by expectation in the dorsal and ventral striatum: dopamine release in the putamen was related monotonically to expected reward value, whereas dopamine released in the ventral striatum reflected the uncertainty of benefit or the salience of the expectation. The placebo effect in PD therefore involves at least two related but separate mechanisms: the expectation of benefit itself, which is scaled to reflect the value of the drug to the patient and is mediated by nigrostriatal dopamine, and the uncertainty or salience of benefit that is mediated by mesolimbic dopamine.

Parkinson�s disease is a neurodegenerative disorder, which is typically characterised in terms of its debilitating effects on motor function. However, ubiquitous neuropsychological deficits are also an integral feature of the progression of this disease. This thesis investigated these cognitive deficits as they manifest in language, with the overarching goal being to elucidate the word-finding problems that are associated with Parkinson�s disease. Making semantic judgements and identifying semantic relations are two processes that are particularly germane to word-finding. Therefore, the present thesis examined: 1) the ability of people with Parkinson�s disease to make judgements about semantic categories, and 2) the integrity of associative semantic networks in Parkinson�s disease. In the first series of studies, Cups and Bowls, a novel semantic categorisation task was used to investigate the ability of people with Parkinson�s disease to consistently categorise common kitchen items across a number of trials. The Parkinson�s group was impaired relative to an age-matched control group on this task. This inconsistent categorisation was particularly apparent for the less typical category exemplars at the category boundaries, suggesting that the Parkinson�s group had less salient or less elaborated semantic categories, which particularly compromised categorisation of the less typical category exemplars. This finding is discussed in terms of selective attention deficits and inappropriate weightings of semantic features. In the second series of studies, Verbal Memory, the structure of the semantic network and access to the semantic system were further investigated using a verbal memory task, which required participants to recall word lists. These word lists consisted of semantically associated words and were designed to elicit false recall of another, non-presented, close semantic associate (the critical lure). The results of this second series of studies, particularly the fact that the Parkinson�s group recalled more of the false critical lures than the control group, suggested an intact semantic network in Parkinson�s disease and normal saliency of semantic categories. The potentiated false recall effect in the Parkinson�s group is discussed in terms of poor modulation of attention in Parkinson�s disease, both as the result of an executive deficit leading to poor controlled processing and in terms of a dopamine-modulated decrease in the signal-to-noise ratio leading to impaired automatic processing. Taken together, the results reported in the present thesis suggest that basal ganglia pathology and striatofrontal deafferentation in Parkinson�s disease do not diminish the integrity of semantic memory, but do compromise operation of semantic memory due to impaired modulation of activation/inhibition mechanisms. This finding of a selective attention deficit has implications for word-finding, suggesting that the word-finding difficulties associated with Parkinson�s disease are the result of impaired lexical access. In particular, retrieval of specific lexical items from semantic memory is impeded because of failure to modulate activation/inhibition mechanisms effectively for the target word to be distinguished from close semantic associates. An intact semantic checking mechanism in anterior language cortex prevents the production of semantic paraphasias, and results in the tip-of-the-tongue word-finding problems displayed by some people with Parkinson�s disease.

Thesis (M.App.Sc. in Physiotherapy)--University of South Australia, 1997.

Thesis (MAppSc in Physiotherapy) -- University of South Australia, 1993

Parkinson???s disease (PD) is a progressive neurodegenerative disease characterised pathologically by the selective death of the dopaminergic neurons of the substantia nigra and the appearance of abnormal inclusions in some surviving neurons. A body of evidence from epidemiological, in vitro and in vivo studies suggest that isoprenoids, a lipid family which includes cholesterol, dolichol and ubiquinone, may play a role in PD, although to date the data has been conflicting with little consensus regarding the type or direction of change in isoprenoids in PD. The current study investigated isoprenoids in PD by quantifying a range of isoprenoids in blood sera, brain homogenates and olfactory mucosa derived from PD patients and controls. Further, isoprenoid synthesis pathways were investigated by comparing the activitites and amount of the rate-limiting enzyme for isoprenoid synthesis, HMG CoA reductase, in olfactory mucosal cultures from individuals with sporadic PD and leucine-rich repeat kinase 2 (LRRK2)-PD with those from healthy individuals. Serum levels of total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides and dolichol were unchanged in patients with PD compared with controls. Similarly, total tissue cholesterol was unchanged in degenerating and non-degenerating regions of the PD brain, but tissue dolichol was significantly decreased in the substantia nigra in the PD brain, possibly reflecting a change in the neuron/glia ratio in this brain region. In olfactory mucosa, a significant decrease in cellular cholesterol content was identified in patients with LRRK2-PD compared with patients with sporadic PD or controls. The reduction in cholesterol was similar in two different LRRK2 mutations but was not associated with a change in either the amount or activity of HMG CoA reductase. This study suggests that decreased cholesterol is associated with LRRK2-PD but not with sporadic PD. As cholesterol levels in cells with different LRRK2 mutations were reduced to a similar extent, it is suggested that mutations in this gene result in a loss-of-function of LRRK2 protein. Further it suggests a role for LRRK2 in cholesterol homeostasis independent of HMG-CoA reductase-associated pathways. Recent data has suggested a functional role of LRRK2 in autophagy, a mechanism which may explain the reduction in cholesterol observed in LRRK2-PD.

Safe and efficient swallowing requires integrity of both motor and sensory systems. Prior studies have established that motor impairment in individuals with PD frequently manifests as abnormalities in swallowing biomechanics. In contrast, very few studies have investigated the contribution of sensory impairment towards pharyngeal biomechanics and airway protection in this patient cohort. This area should be addressed in light of evidence that the severity of limb motor dysfunction in PD does not reliably predict severity of dysphagia. Emerging data suggests that dysphagia in PD cannot be solely attributed to motor impairment, but may also be influenced by deficits in sensory aspects of airway protection. As an example, silent aspiration in up to 100% has been reported in individuals with PD due to laryngopharyngeal sensory deficits have. Even so, current research lacks information on the integration of both motor and sensory components that make up the swallowing process. The aim of this study was to document changes in airway protection with age, in PD and across severity levels of PD. The project was comprised of two parts. In part one, three parallel studies were conducted to assess a series of both motor and sensory airway mechanism (Chapters 4 to 9). In the first study, 16 young (8 males, age range 21.3 - 32.4) and 16 elder adults (8 males, age range 61.5 - 84.7), were assessed to investigate changes in airway protection that accompany ageing. In the second study, data from individuals diagnosed with PD across severity levels (Hoehn-Yahr 1 - 4, age range 64.2 - 84.5) were age and gender-matched to 16 healthy elders in order to examine the effects of PD on airway protection. In the third, the impact of disease severity was studied with data from 16 individuals in the earlier stages (Hoehn-Yahr ≤ 2, 13 males, age range 51.3 - 82.5, ) compared to 16 individuals in the later stages (Hoehn-Yahr ≥ 2.5, 10 males, age range 61.5 - 78.9). In part two of this project, two smaller, pilot studies were completed to probe the influence of pharmacologic and behavioural treatments on airway protection mechanisms. In the first pilot study, the effect of pharmacotherapy on airway protection was investigated in 10 patients 'on' and 'off' levodopa (Chapter 10). In the second study, 5 patients were assessed before and after completing the Lee Silverman Voice Treatment (LSVT) to document effects of speech rehabilitation on airway protection (Chapter 11). Multimodality assessment elicited data from all participants on both motor and sensory components of airway protection (Chapter 3). Specifically, breathing-swallowing coordination (BSC) and swallowing apnoea (SA) were captured using simultaneous directional nasal airflow and surface electromyography (sEMG). Standard, closed-loop spirometry was used to assess pulmonary function. Swallowing biomechanics were screened using a validated timed test of swallowing efficiency and further evaluated using fibreoptic endoscopic evaluation of swallowing (FEES). Finally, chemo-sensation of the laryngopharynx was determined with the administration of the inhalation cough challenge while mechanosensation was examined using FEES. Results suggest that motor control for airway protection is reasonably robust in PD, although sensory response is impaired. The predominant pattern for swallowing respiratory coordination was mid-expiration for all participants regardless of age and disease severity (Chapter 4). Individuals with PD demonstrated a reduction in average time and volume per swallow, leading to an overall decrease in swallowing capacity (Chapter 5). No difference was found for swallowing efficiency between those in early and later stages of PD. Pulmonary function measures were not significantly different as a function of age, PD or PD severity (Chapter 6). In summary, results from motor assessments contributing to airway protection support the robustness of breathing-swallowing coordination (BSC) and pulmonary function across research groups, but identify a reduction in overall swallowing efficiency in PD. Results from sensory assessments contributing to airway protection revealed that chemosensation was not different between age groups but base of tongue mechano-sensation was diminished in individuals with PD. Natural cough thresholds did not differ between young adults and elders but when asked to stifle coughing, elders were less able to do so compared to young adults (Chapter 7). For the first time, a reduction in mechano-reception at the base of tongue was recorded in individuals with PD (Chapter 8). These patients also demonstrated increased post swallow residual (Chapter 5), which offers an explanation for the complaint of globus in this population. These assessments highlight some compromise to sensory aspects of airway protection in PD. Overall, dysphagia had a negative impact on the quality of life of individuals with PD and even more as disease severity progresses (Chapter 9). Results from part two of the study looking at the effects of therapeutic interventions on airway protection revealed some unexpected findings. In chapter 10, results showed a reduction in pulmonary function when 'on' levodopa, but no differences in swallowing efficiency, BSC, or laryngopharyngeal chemo- and mechano-reception were observed. These results suggested a reduction in pulmonary function with levodopa without any increase in risk of airway protection compromise1. Unexpectedly and documented for the first time, the percentage of post swallow inspiration increased after LSVT (Chapter 11) but as with the levodopa study, this was also not accompanied by any apparent increase in aspiration risk. An increase in submental surface electromyography (sEMG) amplitude across all 5 participants may serve as a proxy measure of improvement in hyolaryngeal excursion. Finally, participants reported an overall improvement in social functioning and communication after LSVT. In conclusion, this study provided evidence that mechano-sensory aspect of airway protection is diminished in individuals with PD, possibly compromising airway protection. Patients not only demonstrated increased residue but the lack of sensation may prevent clearing or spontaneous multiple swallows. Overall, airway protection is maintained in ageing but swallowing efficiency declines in the presence of PD. This study contributes significantly to current research efforts in PD by expanding on existing reports regarding motor aspects of airway protection. Specifically, BSC, swallowing efficiency and evaluation of biomechanics using FEES research have never before been investigated exclusively in the PD population. Finally, the chemo- and mechano-sensation evaluated in this study are an important addition to the limited evidence that sensory impairment in individuals with PD potentially compromises airway protection. Results of the present study will serve as a platform upon which future studies may compare and expand.

Thesis (M.Psych./Ph.D.)--University of Western Australia, 2006.

Thesis (BA(Hons) (Psychology)) - Faculty of Life and Social Sciences, Swinburne University of Technology, 2006. / "October 2006". A thesis is submitted in fulfillment of the requirements for the degree Bachelor of Arts (Honours), [Faculty of Life and Social Sciences], Swinburne University of Technology - 2006. Typescript.

Thesis (Ph.D.) - University of Glasgow, 2007. / Ph.D. thesis submitted to the Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow, 2007. Includes bibliographical references.

Thesis (M.Sc.). / Written for the Dept. of Chemistry. Title from title page of PDF (viewed 2008/12/07). Includes bibliographical references.