Neurophysiology of movement transitions in Parkinson's disease with freezing of gait

Abstract Freezing of gait (FOG) is characterized by episodes during which an individual is unable to step, despite intending to do so, and is a common cause of falls, decreased mobility, and increased morbidity in people with Parkinson’s disease (PD). Effective treatment for FOG remains elusive, due to a lack of understanding of the

complex underlying pathophysiology. The expression and factors contributing to FOG are highly heterogeneous across individuals, however, a common feature is that episodes are predominantly triggered during movement-state transitions (e.g. initiating walking or turning)4,5. Impaired transitions leading to FOG

typically occur when the change in movement-state is self-initiated (uncued), but when the same transition is cued by an external sensory stimulus, movement execution is improved, and the incidence and duration of FOG is markedly reduced. FOG may be caused by abnormal communication between subcortical systems

controlling posture and balance (e.g. vestibulo- and reticulospinal systems) and cortico-fugal systems driving the initiation of the intended action (e.g. stepping). Currently, the mechanisms contributing to impaired self-initiated movement transitions in people with PD and FOG, and how they are improved by external cues,

are poorly understood. We hypothesize that the capacity to downregulate the communication (coherence) of systems controlling posture and balance during self-initiated transitions from one movement state (standing) to another (walking) is impaired in people with FOG, and that sensory cues ameliorate FOG by restoring

transition-related modulation of posture/balance systems. This hypothesis will be tested using biomechanical and neurophysiological measures to examine the dynamics of the vestibulo-postural (Aim 1), cortico-cortical and cortico-muscular (Aim 2), and cortico-basal ganglia (Aims 3 and 4) systems during cued and uncued

posture-locomotion transitions in PD, with and without FOG, and controls. Aim 1 will examine the vestibulo-postural system in FOG by measuring the dynamic changes in coherence between vestibular input (electrical vestibular stimulation) and the ground reaction forces controlling balance. Aim 2 will utilize

high-resolution electroencephalography (EEG) and electromyography (EMG) to examine movement-related cortical potentials and cortico-cortical and cortico-muscular coherence. Aim 3 will use EEG and local field potential (LFP) recordings from implanted Medtronic PerceptTM deep brain stimulators (DBS) to examine the

interaction of the globus pallidus and cortex (cortico-pallidal coherence). Aims 1-3 will utilize standardized gait initiation paradigms that may or may not provoke freezing. Aim 4 will use wearable sensors and a FOG-provoking course, involving multiple posture/gait transitions, to wirelessly capture LFPs associated with

FOG episodes in participants with PD with the PerceptTM DBS system. This project will provide insight into the mechanisms and neurological biomarkers of FOG, which will be critical for the development of interventions to reduce the incidence and severity of FOG, reduce falls, and improve the quality of life of people with PD.