Parkinson?s Disease (PD) is a common neurodegenerative disorder affecting human movements. PD is not just a motor disease. It also results in impaired multi-sensory processing that is critical for encoding self- orientation and self-motion. Ultimately, this leads to abnormal spatial navigation, lateral drifts while walking (veering), postural instability and falls in about 70% of patients. Conventional pharmacotherapy or deep brain stimulation (DBS) for PD are variably effective in treating these debilitating symptoms. DBS improves balance dysfunction in some patients, while in some it does not affect balance or even makes it worse. Defining consistent therapy requires a proper understanding of the mechanisms of navigational impairments in PD, and to know how DBS modulates the balance function. A singular vision of our research program is: 1) To reveal the physiological underpinnings of how DBS modulates the process by which multisensory integrated systems govern perception of one?s own motion critical for spatial navigation, gait and balance in PD. 2) To be able to consistently treat navigational impairments such as veering in PD patients with subthalamic nucleus (STN) DBS while preserving its other benefits of treating tremor and increased muscle tone, and reducing pharmacotherapy burden with bothersome side effects. With this goal the current Merit Review application focuses on the vestibular system ? the critical system for the perception of one?s own linear motion, i.e. vestibular heading perception ? the task that is has to be accurate for the proper control of balance, navigation, and averting falls. We hypothesize that effects of STN DBS on vestibular heading perception and veering are dependent upon the specific location of the active electrode contact within the STN and modulation of the cerebello-thalamic pathway that is known to carry the vestibular signal and is in physical vicinity of the STN. In order to test this hypothesis we will objectively measure one?s ability to perceive direction of linear motion (i.e., vestibular heading perception), lateral drifts while walking (i.e., veering) that is common in PD, and then we will compare these objective measures among three independent conditions ? dorsal STN DBS, ventral STN DBS, and DBS off.
The Aim 1 will examine the effects of the location of volume of tissue activation within the STN on the change in vestibular heading perception and veering in human PD patients. We will collate physical location of the volume of tissue activation from all patients when the change in vestibular heading perception and veering was found. These locations, generating the probabilistic stimulation atlas, will provide insights about areas of STN that could influence balance function in PD.
The Aim 2 will examine the recruitment metrics of the axonal pathways modulated by the STN DBS that correlates with change in vestibular heading perception and veering in PD patients. It will directly examine the role of involvement of cerebello-thalamic pathway that is known to transmit vestibular perception information and is in vicinity of the STN. In summary, by taking a top-down approach and leveraging a multidisciplinary team of investigators studying human PD patients with STN DBS, neuroimaging, and computational modeling; we will unravel mechanisms through which STN DBS modulates the vestibular heading perception in PD. Finally we will apply this mechanistic understanding to design consistent and effective therapeutic strategies utilizing DBS to prevent falls in PD.

Public Health Relevance

This work is directly applicable to the health, well-being, and functional independence of disabled Veterans suffering from a devastating and currently incurable neurological condition called Parkinson?s disease ? a neurodegenerative disorder, affecting about 10 million individuals worldwide, including approximately 80,000 US Veterans. Our goal is to define the most effective therapeutic approach utilizing deep brain stimulation and address balance and falls in Parkinson?s disease. Our top-down approach will unravel the anatomical pathways and physiological processes through which we will better understand multi-sensory governance of motion perception critical for spatial navigation, and maintenance of balance and prevention of falls in Parkinson?s disease.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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Louis Stokes Cleveland VA Medical Center
United States
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