Exploring the Neural Mechanisms underlying Freezing of Gait in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder that affects 1-2% of the elderly population. The majority of PD patients develop freezing of gait (FOG), when they experience a sudden cessation of forward progression of the feet despite the intention to walk. FOG causes frequent falls and impacts on the patient’s mobility and independence. FOG results from pathophysiological mechanisms in the brain that are poorly understood, which makes FOG a particular challenge to treat. The overall aim of this thesis is therefore to improve our understanding of the processes underlying FOG in PD and guide adequate treatment development for this devastating symptom. In particular, the processes underlying key concomitant (i.e. motor automaticity impairments and limbic circuit dysfunctions), provoking (i.e. turning) and alleviating (i.e. sensory cueing) factors are investigated. Developments in the clinical management of FOG are then reviewed to establish a set of recommendations to guide future treatment development. The methodology makes use of a Virtual Reality paradigm (VR) in conjunction with functional Magnetic Resonance Imaging (fMRI). The VR partly overcomes the movement restrictions inherent to fMRI while allowing for the investigation of the neural mechanisms underlying lower limb motor control and sensorimotor feedback. The findings suggest that FOG in PD is associated with functional deficits across the frontal and parietal cortices; the basal ganglia; and the brainstem and cerebellar locomotor regions. It is further recognized that the future management of FOG would require specific neuronal and motoric markers to tailor personalized treatments that can operate in an on-demand manner. It is hoped that the insights gained into the neural circuit deficits underlying FOG and the recommendation of a common approach to advance future treatments will ultimately translate in this thesis into improved treatment strategies for this highly burdensome feature of PD.