Difficulties with walking, or gait, can be one of the most disabling symptoms of Parkinson's disease (PD). "Freezing of gait" is a specific problem in which patients are suddenly unable to start or continue walking, often described as a sensation of the feet being "stuck to the ground." It is particularly disabling because it commonly causes falls and loss of independence, and unlike some other gait problems, medications and other therapies often do not improve freezing. Parkinson's disease alters the function of brain circuits involved in walking and other complex movements. While we know that patients with freezing of gait have abnormal activity in several different parts of the brain as compared to patients without freezing, little is known about how this abnormal activity relates directly to the onset and recovery from the freezing episodes themselves because it has historically been difficult to study neural activity during walking. This knowledge gap is an important reason for lack of an effective treatment for FOG. Furthermore, different patients exhibit freezing in different circumstances, and the reasons for this heterogeneity are also poorly understood.

The objective of this proposal is to improve our understanding of how dysfunction in different brain circuits relates to specific types of freezing of gait to inform the development of future therapies. New technologies have recently made it possible to record neural activity (brain waves) using electroencephalography (EEG) during walking and to characterize detailed movement kinematics simultaneously. In this proposal we capitalize on these advances to study brain activity associated with freezing episodes while carefully defining their subtypes using a real-world walking task with multiple different circumstances that provoke or improve freezing. The recordings are obtained non-invasively with wearable sensors on the limbs and an electrode cap on the head while patients (with and without freezing of gait) and healthy controls walk in a clinic setting. Risks are minimal and include fatigue from walking, potential for falls (which will be mitigated by close monitoring by experimenters) and discomfort from being off of Parkinson's medications during the experiment. There are no direct benefits to participants, but potential benefits include the development of more effective therapies for freezing of gait in the future. The results of these studies will provide a foundation for developing therapies that target specific brain signals associated with subtypes of freezing. The development of these novel therapies would require clinical trials, which occur over several years. Freezing of gait affects 50%-80% of patients with advanced disease, and some patients with earlier disease as well. In many of these patients it is a primary cause of disability. Therefore, improved therapies for freezing would have an impact on a relatively large portion of the population suffering from PD and, in particular, more advanced patients.

The principal investigator (PI) of this proposal is a physician-scientist with training in Movement Disorders neurology and research experience in a variety of human brain mapping techniques applied to understanding motor and cognitive function in health and disease. Her career goals are to apply her training in systems neuroscience to the study of motor and cognitive symptoms in Parkinson's disease. She has a particular interest in understanding individual differences and disease heterogeneity in real-world settings, as this will provide unique insight into specific symptoms and allow for more targeted treatment approaches. The research plan will provide training in mobile EEG which, unlike most brain mapping methods, allows for brain recordings during real world movement tasks relevant to many areas of PD research. In addition, it will develop her expertise in kinematics and biomechanics, which allow detailed characterization of movements -- essential to relating brain activity to specific symptoms. Training will be supported by the mentorship of Dr. Nader Pouratian, a Professor of Neurosurgery and Director of the Neurosurgical Movement Disorders program at UCLA. He is a bioengineer and has published extensively on neural mechanisms of movement abnormalities in Parkinson's disease. He will provide direct hands-on training in data collection and analysis and provide invaluable career advice informed by his own successful pursuit of research funding and collaborative neuroscience. In addition, the researcher development plan includes coursework to fill gaps in gait biomechanics as well as collaboration with Dr. Nanthia Suthana, who has developed and applied technologies for mobile neural recordings in real-world settings. Together, the mentorship and researcher development plan will prepare the PI to establish an independent research program in studies of cognitive and motor features of gait dysfunction in PD using state-of-the-art technologies.