Freezing of gait in Parkinson’s disease is related to imbalanced stopping-related cortical activity

Abstract Freezing of gait, characterized by involuntary interruptions of walking, is a debilitating motor symptom of Parkinson's disease that restricts people's autonomy. Previous brain imaging studies investigating the mechanisms underlying freezing were restricted to scan people in supine positions and yielded conflicting theories regarding the role of the supplementary motor area and other cortical regions. We used functional near-infrared spectroscopy to investigate cortical haemodynamics related to freezing in freely moving people. We measured functional near-infrared spectroscopy activity over multiple motor-related cortical areas in 23 persons with Parkinson's disease who experienced daily freezing (‘freezers’) and 22 age-matched controls during freezing-provoking tasks including turning and doorway passing, voluntary stops and actual freezing. Crucially, we corrected the measured signals for confounds of walking. We first compared cortical activity between freezers and controls during freezing-provoking tasks without freezing (i.e. turning and doorway passing) and during stops. Secondly, within the freezers, we compared cortical activity between freezing, stopping and freezing-provoking tasks without freezing. First, we show that turning and doorway passing (without freezing) resemble cortical activity during stopping in both groups involving activation of the supplementary motor area and prefrontal cortex, areas known for their role in inhibiting actions. During these freezing-provoking tasks, the freezers displayed higher activity in the premotor areas than controls. Secondly, we show that, during actual freezing events, activity in the prefrontal cortex was lower than during voluntary stopping. The cortical relation between the freezing-provoking tasks (turning and doorway passing) and stopping may explain their susceptibility to trigger freezing by activating a stopping mechanism. Besides, the stopping-related activity of the supplementary motor area and prefrontal cortex seems to be out of balance in freezers. In this paper, we postulate that freezing results from a paroxysmal imbalance between the supplementary motor area and prefrontal cortex, thereby extending upon the current role of the supplementary motor area in freezing pathophysiology.