We aim to provide a better understanding of the pathophysiology underlying FOG, as a basis for development of improved and rationally based treatment strategies. To achieve this, we will use two new approaches. In Project A, we aim to develop a new approach to reliably elicit FOG in a gait laboratory. Here, our specific research questions are: (a) Does the need to suddenly avoid obstacles provoke FOG during walking on a motorized treadmill? (b) Does walking on a split-belt treadmill (which can induce subtle differences in step timing between both legs) provoke FOG?In Project B, we will explore the cerebral substrate that is associated with FOG. Here, our specific research questions are: (a) Do PD patients use different cerebral circuits for planning of gait compared to healthy controls? (b) Is FOG associated with specific alterations in cerebral activity or with changed connectivity between cerebral regions? (c) Which changes in cerebral activity of patients with PD reflect the primary disease process (i.e. causally related to their walking problems), and which could reflect increased (compensatory) neural activity intended to support the ability to walk? Freezing of gait (FOG) is a common, disabling, but still largely mysterious feature of Parkinson s disease (PD). FOG it is an episodic gait disorder: during walking or turning, the feet become suddenly and unpredictably glued to the floor, frequently leading to falls. Development of improved therapeutic strategies is urgently needed, but this calls for a much better understanding of the underlying pathophysiology. However, more detailed pathophysiological studies are hampered by the fact that FOG episodes are notoriously difficult to elicit in a laboratory setting, perhaps because anxiety suppresses FOG. Moreover, it is difficult to study which cerebral activations might cause FOG because traditional neuroimaging methods are not suitable to study gait. Here, we aim to tackle this problem using new and validated approaches to study the pathophysiology underlying FOG in patients with PD. We will use two complementary but interrelated approaches: gait analysis during treadmill walking, to obtain new insights in FOG at the behavioural level; and functional MRI during imagined walking, to investigate neuronal activity related to FOG. In Project A, we will use new methods to provoke FOG in patients walking on a motorized treadmill, allowing us to perform more detailed quantitative studies in a reliable and controlled experimental setting. We will capitalize on our pilot observation that FOG can be induced by the need to avoid suddenly appearing obstacles. Moreover, we will test a new hypothesis, namely that FOG may primarily relate to a problem with the temporal coordination of motor performance between the two legs. For this purpose, we will use a split-belt treadmill and ask patients to walk while manipulating the difference in speed of the treadmills for each leg. This project might identify the environmental cues and the motor control parameters that are crucial for triggering FOG.In Project B, we will examine modifications of cerebral activity associated with FOG, using a recently validated psychophysical protocol where subjects are asked to imagine walking along paths of variable distances and width. This approach will allow us to test whether PD patients use different cerebral circuits for planning gait compared to healthy controls; and whether, within the group of PD patients, specific cerebral alterations can predict FOG symptomatology. This project might identify brain areas with altered activity and/or connectivity specifically associated with FOG. This research proposal combines an innovative approach with state-of-the-art equipment. All research projects are supported by extensive pilot work and an experienced research team. The results are expected to shed new light on the pathophysiology underlying FOG, and provide a framework for future studies aiming to develop new treatments tailored to pathophysiological insights, for example using non-invasive cortical stimulation techniques.