Investigating the mechanism of action of Deep Brain Stimulation using functional magnetic resonance imaging

Depleted of dopamine, the dynamics of the Parkinsonian brain impact on both “action” and “resting” motor behaviour. Subthalamic nucleus deep brain stimulation (STN DBS) has become an established means of managing these symptoms, although its mechanisms of action remain unclear. Functional magnetic resonance imaging (fMRI) using the blood oxygen level dependent (BOLD) contrast provides the opportunity to study the human brain in vivo, collecting indirect measures of neural activity across the whole brain. To date, technical difficulties and safety concerns have precluded the use of fMRI in DBS patients. Previous work from this department has demonstrated that scanning patients with certain DBS systems and MRI equipment is both safe and feasible. This thesis explores the neuromodulatory actions of STN DBS on both action and resting motor behaviours in patients with Parkinson’s disease (PD) using fMRI. In brief, I present two fMRI studies conducted on STN DBS patients, one task-based, and one resting, collected under a previously approved protocol. I then present experiments exploring the safety of scanning DBS patients using an improved protocol, and then detail two further experiments collected under this new protocol, again one task-based, and one resting. Specifically, I employ statistical parametric mapping to determine DBS-induced changes in motor evoked responses. Using dynamic causal modelling (DCM) and Bayesian model selection, I compare generative models of cortico-subcortical interactions to explain the observed data, inferring which connections DBS may be affecting, and which modulations predict efficacy. I proceed to use stochastic DCM to model the modulatory effects of DBS on endogenous (resting-state) dynamics. Abstract | 4 4 This work casts DBS in terms of modulating effective connectivity within the cortico-basal ganglia motor loops. I discuss how this may explain its current usage in PD, as well as exploratory uses to treat other pathological brain states