A Jon Stoessl
Relevant Thesis-Based Degree Programs
Affiliations to Research Centres, Institutes & Clusters
Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Objective: Exercise has been shown to be beneficial for people with Parkinson’s disease (PD) however, the underlying mechanisms are unknown. Evidence from animal models has shown exercise-induced changes in the dopaminergic system and decreased neuroinflammation, but these changes have yet to be studied in patient populations. The purpose of this thesis was to study the effects of exercise on dopaminergic function and neuroinflammation using multimodal neuroimaging in subjects with PD. Methods: Two different comparisons were conducted using positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). First, a cross-sectional study compared dopamine release, and ventral striatal activity, between PD habitual exercisers and sedentary PD subjects. Next, a prospective trial was conducted to compare the effects of exercise on ventral striatal activity, dopamine release and neuroinflammation. Results: The cross-sectional study showed that habitual exercisers have greater dopamine release in the caudate nucleus in response to exercise and greater activation of the ventral striatum in response to monetary reward, compared to sedentary PD subjects. Similarly, the prospective trial showed increased dopamine release in the caudate nucleus in response to repetitive transcranial stimulation after 3 months of aerobic exercise compared to a stretching control group. Moreover, the aerobic group showed increased activity of the ventral striatum in response to monetary reward, compared to the control group. The aerobic group also showed decreased neuroinflammation in the thalamus, globus pallidus and cerebellum, but those findings were highly dependent on the type of analysis method used and technical limitations of the PET tracer. Conclusion: The benefits of exercise in PD are likely driven by changes to the dopaminergic system. Aerobic exercise increased dopamine release in the caudate nucleus and increased responsivity in the ventral striatum, suggesting changes to the dorsal striatum and mesolimbic dopaminergic system. The exercise-induced changes in neuroinflammation are limited to the analysis methods and technical constraints of imaging neuroinflammation. Collectively, the findings of this thesis support the use of exercise as an adjunct therapy for PD by showing that the benefits of exercise in PD are the result of neurological changes to the dopaminergic system.
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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.
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Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Parkinson’s disease (PD) is the second most common neurodegenerative disorder globally, following Alzheimer’s Disease. Numerous proposed mechanisms aim to explain the pathogenesis of this degenerative condition; however, none currently accounts for the selective vulnerability seen in PD. That is, dopaminergic projections to the dorsal and caudal striatum degenerate first and maximally, followed by more rostral and ventral regions. While a caudal torostral pattern of progression is supported by previous molecular imaging studies, the possibility of an additional dorsal to ventral gradient is less established. If such a gradient exists, one would expect to see initial PD motor symptoms in the lower limbs, based on the somatotopic mapping of the body within the central nervous system, however this is not in keeping with typical clinical observations. Patients often present with initial impairments in the arm or hand, although this could be possibly explained by greater sensitivity to functional deficits involving fine hand dexterity. Furthermore, loss of dopamine may lead to altered signal to noise ratio in striatal projection neurons, reducing somatotopic segregation in the striatum and its connections. Cortico-striatal loops are thought to be segregated according to function (motor, associative,limbic etc.) and body region. Based on studies of repetitive transcranial magnetic stimulation-evoked dopamine release, it has been suggested that cortical stimulation results in an anatomically broader release of dopamine within the striatum in PD, but of lower magnitude than in the healthy state. The aim of the larger research initiative covered in this thesis was to study the altered striatal plasticity in early-stage PD (less than 5 years duration) and delineate the functional reorganization of dopaminergic projections in PD neurodegeneration. To do this, novel hybrid positron emission tomography and magnetic resonance imaging with [¹¹C]raclopride was utilized to simultaneously assess patterns of dopamine release and striatal activation induced by behavioural tasks involving the various corticostriatal loops in PD andhealthy control subjects. The primary focus of this thesis was on a subset of these tasks specifically designed to activate the sensorimotor pathway; finger and foot tapping tasks.
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Repetitive head trauma is a known cause of tau protein accumulation and the leading cause of chronic traumatic encephalopathy (CTE). Currently, no robust method for in vivo detection of CTE exists and definitive diagnosis can only be made post-mortem. This thesis aimed to address two gaps in the literature surrounding head injury and tau accumulation. First, we sought to evaluate the effects of concussion on adolescent brain structure using mathematical modeling applied to diffusion tensor imaging (DTI). In our study, 12 adolescent athletes completed DTI in the sub-acute phase of recovery from concussion. The primary outcome measures included Complex Network Analysis metrics related to efficiency, nodal clustering, and fibre tract length. These measures were applied to diffusivity output (FA, MD, and number of tracts) in subnetworks of vulnerability, with specific focus on the Default Mode Network (DMN). Here we found microstructural changes in the DMN of concussed athletes with increased clustering and shorter path lengths, indicating increased local efficiency. A corresponding decrease in global efficiency and alterations in core hubs may underlie the clinical profile, suggesting concussion results in large-scale network disconnection. Longitudinal studies with network analysis may serve as a marker of collective injury and provide early detection of pathological structural organization. Second, we established the baseline measures of a novel positron emission tomography (PET) radioligand, ¹¹C-PBB3, which is specific for hyperphosphorylated tau protein. We collected data on healthy, elderly individuals (n = 8), and tested the tracer in a probable (n = 1) and severe (n = 1) case of Progressive Supranuclear Palsy (PSP), a known tauopathy. We found that tracer circulated in the venous sinuses in our healthy controls with little to no deposition in brain tissue. We also present preliminary findings of tracer accumulation in the basal ganglia and thalamus in the PSP cases. These results suggest ¹¹C-PBB3 is a viable tracer for use in other tauopathies, including CTE. Longitudinal studies with combined DTI and PET are necessary to elucidate the potentially synergistic interactions between damage to white matter tracts, tau accumulation, inflammation, and the initiation of processes leading to CTE and other tauopathies.
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Exercise can improve symptoms of Parkinson's disease (PD), including bradykinesia, balance, cognition and quality of life, but the therapeutic mechanisms of benefit are poorly understood. First, this thesis aimed to fill a gap in the literature through a systematic review on the effects of exercise on cognition in PD. This systematic review identified the benefits of exercise for cognition, but found studies seldom involved an intervention over 12 weeks, and few human studies investigated mechanisms of exercise in PD. Therefore, we next tested our novel research question: what are the effects of long-term regular (i.e., habitual) exercise on PD, and what may be the associated mechanisms of benefit for motor and non-motor symptoms? Our study compared 12 PD subjects allocated to one of two matched cohorts (n = 6 each), differing only in regular exercise levels. The primary outcome was dorsal and ventral striatal dopamine release in response to acute exercise (30 min cycling) measured using PET and displacement of [¹¹C]raclopride (RAC) binding potential (BP). The secondary outcomes were response to reward in the ventral striatum measured with BOLD percent signal change (PSC) using fMRI, as well as clinical measures of motor function, cognition, mood and apathy. We found habitual exercisers did not release more striatal dopamine in response to acute exercise. In contrast, we found that habitual exercisers had increased RAC BP in their less affected anterior putamen post-exercise. During the fMRI card task habitual exercisers had greater BOLD PSC compared to baseline and both cohorts had greater activation during the reward phase compared to the anticipation phase. In terms of clinical outcomes, habitual exercisers had greater aerobic capacity (VO₂ peak, confirming cohort allocation), as well as improved finger tapping, peg insertion, faster walking, less depression, more positive affect, and less apathy. In summary, habitual exercise does not affect dopamine release in response to acute exercise, but may impact striatal RAC binding as well as response to reward in the ventral striatum. There may be dopaminergic contributions to the motor and mood benefits from habitual exercise in PD, but this topic requires further study.
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