A Jonathan Stoessl
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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - April 2022)
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.
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.
Master's Student Supervision (2010 - 2021)
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.