Beneath the surface: Functional brain imaging in Parkinson's disease

Parkinson's disease is a neurodegenerative disorder known for its motor symptoms, but it's actually a disease of the brain as a whole, manifesting in many domains of functioning. The goal of this thesis was to provide more insight into the changes in brain function related to disease progression in Parkinson's disease and the effects of deep brain stimulation (DBS) on it. We used imaging techniques that allowed us to measure not only cortical but also subcortical brain activity: Magnetoencephalography (MEG) and functional Magnetic Resonance Imaging (fMRI). Unique to our setup was the ability to investigate the functional effects of DBS through MEG, despite the challenges posed by stimulation artifacts. In the first part of the thesis, we studied changes in brain activity related to disease progression, both regarding cognitive and motor symptoms. We included Parkinson's disease patients from the earliest to the late stages of the disease in our study (disease duration of ~20 years). From the literature, it is known that a slowing in cortical brain activity is strongly (positively) correlated with clinical worsening in both cognition and motor function. In our MEG study, we found that this is the case not only for cortical brain regions but also for subcortical areas. In the subsequent chapters, we further explored the functional changes in subcortical brain areas. We investigated the direction of information flow to and from subcortical brain areas, as well as the role of subcortical areas in executive functioning. In the second part of the thesis, we studied the effect of DBS on brain function, a commonly used therapy for Parkinson's patients. The ultimate question was whether MEG could be used to better predict the effects and potential side effects of DBS. We found that i) Parkinson's patients with a good response to DBS showed an increase in functional connectivity in the beta band after stimulation, ii) post-operative apathy, a common side effect of DBS, was related to a decrease in functional connectivity of the dorsolateral prefrontal cortex when turning on the DBS. Finally, we conducted measurements where we activated a different contact point during each recording (4 per side). We found that it is possible at the group level to measure differences in brain activity related to different stimulation positions: a so-called electrophysiological 'fingerprint' of the STN. However, the findings were still too variable among individuals to draw conclusions about the effects within an individual. The studies in this thesis contribute to a better understanding of the changes in brain activity that occur in Parkinson's disease and its treatment through DBS. A better understanding of these functional changes is important for i) the development of better treatment options, ii) better prediction of the disease course for an individual patient, iii) monitoring the effect of future disease-modifying therapies.