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.

Psychopharmacological studies have implicated the mesolimbic dopamine (DA) system in the mediation of cost/benefit evaluations about effort-related costs associated with larger rewards. However, the role of DA in risk-based decision making remains relatively unexplored. The present study investigated how systemic manipulations of DA transmission affect risky choice assessed with a probabilistic discounting task. Over discrete trials, rats between two levers; a press on the “small/certain” lever always delivered one reward pellet, whereas a press on the other, “large/risky” lever delivered four pellets, but the probability of receiving reward decreased across the four trial blocks (100%, 50%, 25%, 12.5%). In separate groups of well-trained rats we assessed the effects of the DA releaser amphetamine, as well as receptor selective agonists and antagonists. Amphetamine consistently increased preference for the large/risky lever; an effect that was blocked or attenuated by co-administration of either D₁ (SCH23390) or D₂ (eticlopride) receptors antagonists. Blockade of either of these receptors alone induced risk aversion. Conversely, stimulation of D₁ (SKF81297) or D₂ (bromocriptine) receptors also increased risky choice. In contrast, activation of D₃ receptors with PD128,907 induced risk aversion. Likewise, D₃ antagonism with nafadotride potentiated the amphetamine-induced increase in risky choice. Blockade or stimulation of D₄ receptors did not reliably alter patterns of choice. These findings indicate that DA plays a critical role in mediating risk-based decision making, where increased activation of D₁ and D₂ receptors biases choice towards larger, probabilistic rewards, whereas D₃ receptors appear to exert opposing effects on this form of decision making.

As wireless devices are becoming more powerful, more flexible and less costly to produce, they are often being applied in new ways. Combining wireless technology with new types of sensors results in the ability to monitor and control the environment in ways not previously possible. For example, an intelligent wireless sensor system that consists of a sensor, digital processor and a transceiver can be mounted on a board the size of a coin. The data collected by these devices are then transmitted to a central unit which is able to thoroughly process and store this data. Not only can the central processing station provide reports about certain physical parameters in the environment, it can also control the environment and other parameters of interest. The design process of these wireless sensor platforms is a well-developed area of research that covers concepts like networking, circuit design, Radio-Frequency (RF) circuits and antenna design. The design of a wireless sensor can be as simple as putting together a microcontroller, a transceiver and a sensor chip or as complicated as implementing all the necessary circuitry into a single integrated circuit. One of the main applications of the sensors is in a control loop which controls physical characteristics in an environment. Specifically, if the objective of a control system is to limit the amount of vibrations in a structure, vibration sensors such as accelerometers are usually used. In environments where the use of wires is costly or impossible, it makes sense to use wireless accelerometers instead. Among the numerous applications that can use such devices are the automotive and medical vibration control systems. In the automotive industry it is desirable to reduce the amount of vibrations in the vehicle felt by the passengers. These vibrations can originate from the engine or the uneven road, but they are damped using passive mechanical elements like rubber, springs and shocks. It is possible however, to have a more effective vibration suppression using active sensor-actuator systems. Since adding and maintaining wires in a vehicle is costly, a wireless accelerometer can be put to good use there. A medical application for wireless accelerometers can be used with a procedure called Deep Brain Stimulation (DBS). DBS is a relatively new and very effective treatment for advanced Parkinson’s disease. The purpose of DBS is to reduce tremors in the patients. In DBS a set of voltages is applied to the brain of the patient as some optimum combinations of voltages will have a very positive effect on the tremors. Those optimum voltages are currently found by trial and error while a doctor is observing the patient for tremors. Wireless accelerometers with the use of a computer algorithm can assist in this process by finding the optimum voltages using the feedback provided by the accelerometers. The algorithm will assist the doctor in making decisions and has the potential of finding the optimums completely on its own.

Individuals with Parkinson’s disease (PD) display deficits in voluntary saccade generation but improved automatic, visually-triggered saccade performance. This can be tested using prosaccades, saccades to visual stimuli, and antisaccades, saccades in the opposite direction from the visual stimuli. Voluntary saccade impairments resulting in antisaccade direction errors and longer saccadic reaction times (SRTs) are thought to be due to insufficient presetting of neural circuitry during saccade preparation in complex tasks involving suppression and selection. The basal ganglia, a major site of PD pathology, might be the cause of abnormalities in preparing for action selection in PD patients. Recently, microsaccade rates have been hypothesized to reflect the dual preparatory signals of saccade facilitation and suppression. In this thesis, we investigated the microsaccade behaviour of PD patients as they performed prosaccades and antisaccades. We hypothesized that deficits in voluntary movements in PD would result in impaired suppression of involuntary movements as reflected by increased microsaccade rates. Our findings demonstrate consistently elevated microsaccade rates in PD subjects compared to age-matched controls. Furthermore, positive correlations were found between antisaccade direction error rate and microsaccade rate as well as microsaccade rate and Hoehn-Yahr score, an indicator of disease severity in PD patients. We conclude that microsaccades reflect the impaired suppression of involuntary movements caused by voluntary movement deficits in PD pathology. Our findings indicate that microsaccades provide insight into action preparatory mechanisms and BG dysfunction. Therefore, measuring microsaccades in PD may provide a useful biomarker to follow disease progression and effectiveness of treatment therapies. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2014-01-09 23:31:21.78

α-Synuclein is an abundant nerve terminal protein and a primary component of the Lewy body pathology seen in Parkinson’s disease. While the precise biological and pathological role of α-synuclein remains unclear, its ability to bind to and dissociate from synaptic membranes may be linked to its function in these states. In this thesis, we characterized the role of the GTPase protein rab3a as a potential regulator of α-synuclein membrane binding and dissociation. We found evidence that GTP-bound rab3a sequesters α-synuclein on membranes during exocytosis, and that inhibition of rab3a dissociation from the membrane causes inhibition of α-synuclein dissociation as well. Furthermore, we found that the loss of rab3a in human neuroblastoma cells increases α-synuclein expression. This study identifies rab3a and proteins associated with its membrane dissociation as mediators of α-synuclein membrane binding and dissociation.

α-Synuclein is an abundant nerve terminal protein and a primary component of the Lewy body pathology seen in Parkinson’s disease. While the precise biological and pathological role of α-synuclein remains unclear, its ability to bind to and dissociate from synaptic membranes may be linked to its function in these states. In this thesis, we characterized the role of the GTPase protein rab3a as a potential regulator of α-synuclein membrane binding and dissociation. We found evidence that GTP-bound rab3a sequesters α-synuclein on membranes during exocytosis, and that inhibition of rab3a dissociation from the membrane causes inhibition of α-synuclein dissociation as well. Furthermore, we found that the loss of rab3a in human neuroblastoma cells increases α-synuclein expression. This study identifies rab3a and proteins associated with its membrane dissociation as mediators of α-synuclein membrane binding and dissociation.

Parkinson’s disease (PD) is a neurodegenerative movement disorder and a leading cause of neurological disability in the older adult population. Historically, the research and treatment of PD has focused on the associated motor symptoms. Now the non-motor symptoms such as sleep disturbance are becoming an increased focus for researchers. Deep brain stimulation (DBS) is a surgical intervention that has proven to be beneficial for PD motor symptom management. There are claims from the literature that DBS may assist with the phenomenon of sleep disturbance. A case study analysis was done to explore this concept in the DBS-PD patient population using the framework of the Symptom Management Theory. From the analysis of the subjective and objective data gathered it is clear that the phenomenon of sleep disturbance in this population is multifaceted and that DBS may play a role in managing the phenomenon of sleep disturbance for this population.

Principles of motor learning (PMLs) refer to a set of concepts which are considered to facilitate the process of motor learning. PMLs can be broadly grouped into principles based on (1) the structure of practice/treatment, and (2) the nature of feedback provided during practice/treatment. Application of PMLs is most evident in studies involving non-speech- motor tasks (e.g., limb movement). However, only a few studies have investigated the application of PMLs in speech-motor tasks. Previous studies relating to speech-motor function have highlighted two primary limitations: (1) Failure to consider whether various PMLs contribute equally to learning in both non-speech and speech-motor tasks, (2) Failure to consider whether PMLs can be effective in a clinical cohort in comparison to a healthy group. The present research was designed to shed light on whether selected PMLs can indeed facilitate learning in both non-speech and speech-motor tasks and also to examine their efficacy in a clinical group with Parkinson’s disease (PD) in comparison to a healthy group. Eighty healthy subjects with no history of sensory, cognitive, or neurological abnormalities, ranging 40-80 years of age, and 16 patients with PD, ranging 58-78 years of age, were recruited as participants for the current study. Four practice conditions and one feedback condition were considered in the training of a speech-motor task and a non-speech- motor task. The four practice conditions were (1) constant practice, (2) variable practice, (3) blocked practice, and (4) random practice. The feedback was a combination of low-frequency, knowledge of results, knowledge of performance, and delayed feedback conditions, and was paired with each of the four practice conditions. The participants in the clinical and non-clinical groups were required to practise a speech and a non-speech-motor learning task. Each participant was randomly and equally assigned to one of the four practice groups. The speech-motor task involved production of a meaningless and temporally modified phrase, and the non-speech-motor task involved practising a 12-note musical sequence using a portable piano keyboard. Each participant was seen on three consecutive days: the first two days served as the acquisition phase and the third day was the retention phase. During the acquisition phase, the participants practised 50 trials of the speech phrase and another 50 trials of the musical tune each day, and each session lasted for 60-90 min. Performance on the speech and non-speech tasks was preceded by an orthographic model of the target phrase/musical sequence displayed on a computer monitor along with an auditory model. The participants were instructed to match their performance to the target phrase/musical sequence exactly. Feedback on performance was provided after every 10th trial. The nature of practice differed among the four practice groups. The participants returned on the third day for the retention phase and produced 10 trials of the target phrase and another 10 trials of the musical sequence. Feedback was not provided during or after the retention trials. These final trials were recorded for later acoustic analyses. The analyses focused on spatial and temporal parameters of the speech and non-speech tasks. Spatial analysis involved evaluating the production accuracy of target phrase/tune by calculating the percentage of phonemes/keystrokes correct (PPC/PKC). The temporal analysis involved calculating the temporal synchrony of the participant productions (speech phrase & tune) during the retention trials with the target phrase and tune, respectively, through the phi correlation. The PPC/PKC and phi correlation values were subjected to a series of mixed model ANOVAs. In the healthy subjects, the results of the spatial learning revealed that the participants learned the speech task better than the non-speech (keyboard) task. In terms of temporal learning, there was no difference in learning between the speech and non-speech tasks. On an overall note, the participants performed better on the spatial domain, rather than on the temporal domain, indicating a spatial-temporal trade-off. Across spatial as well as temporal learning, participants in the constant practice condition learned the speech and non-speech tasks better than participants in the other practice conditions. Another interesting finding was that there was an age effect, with the younger participants demonstrating superior spatial and temporal learning to that of the older participants, except for temporal learning on the keyboard task for which there was no difference. In contrast, the PD group showed no significant differences on spatial or temporal learning between any of the four practice conditions. Furthermore, although the PD patients had poorer performances than the healthy subjects on both the speech and keyboard tasks, they showed very similar pattern of learning across all four practice conditions to that of the healthy subjects. The findings in the current study tend to have potential applications in speech-language therapy, and are as follows: (1) a constant practice regime could be beneficial in developing speech therapy protocols to treat motor-based communication disorders (e.g., dysarthria), (2) speech therapists need to exercise caution in designing speech therapy goals incorporating similar PMLs for younger and older adults, as the application of similar PMLs in younger and older adults may bring about different learning outcomes, (3) and finally, it could be beneficial for patients to practise speech tasks which would require them to focus either on the spatial or temporal aspect, rather than focussing on both the aspects simultaneously.

Accumulating evidence suggests that inflammation plays an important role in the progression ofParkinson's disease (PD). Among many inflammatory factors found in the PD brain, cyclooxygenase(COX), especially the inducible isoform, COX-2, is believed to be the critical enzyme in theinflammatory response. Induction of COX-2 is also found in an experimental model of PD producedby administration of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To investigate whetherinhibition of COX-2 by valdecoxib or deficiency in COX-2 could prevent dopaminergic neuronaltoxicity and locomotor activity impairment, we injected MPTP into valdecoxib-treated C57BL/6N miceand COX-2 deficient mice, respectively. Both automated total distance and vertical activitymeasurements of the open-field test were significantly reduced in the vehicle-treated mice at two weekspost-MPTP injection. In contrast, valdecoxib treatment significantly attenuated these deficits.Similarly, COX-2 deficiency attenuated MPTP-induced loss of coordination on a rotarod assay.Valdecoxib or deficiency of COX-2 reduced microglial activation while preventing loss of tyrosinehydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc). The total number ofactivated microglia in the SNpc had a strong positive correlation with the level of COX-2 anddopaminergic neurodegeneration. The results of this study indicate that reducing the activity of COX-2can mitigate the progressive loss of dopaminergic neurons as well as the motor deficits caused byMPTP neurotoxicity, possibly by suppressing the activation of microglia in the SNpc.

Cognitive impairment in Parkinson’s disease (PD) can impact negatively on caregivers and is associated with carer distress and feelings of burden. To investigate this relationship we examined level of burden, coping strategies, depression, anxiety and potential positive aspects of caregiving in the caregivers of 104 PD patients. The PD patients were classified as either showing normal cognition (PD-N; n=57), with mild cognitive impairment (PD-MCI; n=31) or with dementia (PD-D; n=16). The key finding was that mean Zarit burden score increased between carers of PD-N (M=14.1, SD=12.0) through to PD-MCI (M=21.1, SD=9.86) and PD-D (M=27.8, SD=10.61); F (2,101) =9.96, p<0.001. Post hoc tests (Newman-Keuls) identified significantly higher Zarit burden scores in PD-D caregivers compared to both PD-N (p<.001) and PD-MCI patients (p<.05), but carers of PD-MCI patients also showed increased burden scores relative to those of PD-N patients (p<.05). The proportion of carers showing significant levels of burden (Zarit burden score ≥21) also increased as cognition declined (21% for PD-N; 58% for PD-MCI; and 81% for PD-D). Time spent providing care and problem-focused, emotion-focused and dysfunctional coping strategies also increased with worsening cognition. While caregiver use of problem-focused coping mediated the association between patient cognitive status and caregiver burden, we could not be confident about this relationship as the inverse model was also significant. Caregiver Zarit burden was independent of caregiver depression, anxiety and positive attributions of caregiving. The study highlights the impact of Parkinson’s disease on those providing care when the patients’ cognition is poor, including those with MCI. Caregiver well-being has important implications for nursing home placement and disease course.