We will develop a new treatment modality for Parkinson’s disease, neurofeedback with functional magnetic resonance imaging (fMRI) signals, that emulates the effects of deep brain stimulation (DBS) on brain networks. New neuromodulation treatments are needed for in the field of neurodegenerative disorders (as recognised by this call for proposals) - current invasive neuromodulation protocols with DBS provide good symptomatic relief for motor symptoms of Parkinson’s disease (PD) but have inconsistent effects on the often equally disabling non-motor symptoms, whereas the clinical effects of non-invasive brain stimulation techniques have been generally limited so far. In order to emulate the success of DBS on motor symptoms non-invasively we need to measure its effects directly with fMRI and target these fMRI signal patterns with neurofeedback. Similarly, for better relief of non-motor symptoms we need to map the relevant network both functionally and anatomically and identify the relevant neurofeedback targets. Finally we need to show that patients with PD can indeed self-regulate activation in these networks through neurofeedback training. This project will thus include simultaneous DBS-fMRI studies and anatomical connectivity mapping of the cortico-subcortical networks supporting symptom relief, classification analysis of therapeutic activation patterns, and proof of concept of the feasibility of neurofeedback with these signals. In WP (work package) 1 we will scan PD patients during DBS of the subthalamic nucleus (STN) and compare “on” (with motor symptom improvement) and “off” states with classification analysis of functional connectivity patterns. We will also use online fMRI during DBS in patients who show improvement of non-motor symptoms and combine this information with the knowledge of anatomical connectivity of the non-motor portion of the STN. We will then demonstrate proof-of-concept of neurofeedback training targeting these signals in PD patients with a focus on motor symptoms and the non-motor symptoms depression and anxiety (WP2-3). This work will lay the foundation for clinical trials of this promising non-invasive neuromodulation strategy that can be used both in patients without implanted DBS electrodes and as an add-on to DBS.