Sleep dysfunction is a disabling non-motor symptom that adversely affects quality of life in patients with Parkinson's disease (PD) (1-4). Sleep disorders are common, affecting 74-98% of PD patients (1, 5). Deep brain stimulation (DBS) of the sub thalamic nucleus (STN) effectively controls motor symptoms in advanced PD (6-8). Studies (9-15) show that STN DBS, using settings optimized for motor function, also improves sleep in these patients. However, the relationship between DBS parameters and sleep has not been reported, and the most effective stimulator settings for optimizing sleep architecture are not known. Since sleep dysfunction negatively Impacts quality of life in PD patients, it is important to understand the relationship between motor and sleep effects of DBS in order to optimize currently available treatment options for this common non-motor symptom. The proposed research will test the central hypothesis that LOW frequency (60 Hz) unilateral STN DBS improves sleep more effectively than conventional HIGH frequency (?130 Hz) stimulation in PD patients. This hypothesis is based on the idea that LOW frequency STN DBS modulates brainstem activity at locations such as the pedunculopontine nucleus that are important for sleep regulation. To address this hypothesis, the PI will use a within-subject cross-over design evaluating polysomnographic sleep parameters at LOW and HIGH frequency settings in the laboratory setting. The morning following each study, subjects will be assessed for any residual adverse motor effects from sleep-time LOW frequency stimulation (Aim 1). Additionally, the PI will determine if changes in sleep efficiency (as measured in Aim 1) induced by LOW frequency STN DBS Correlate with changes in daytime vigilance through use of a novel endpoint of vigilance in PD, measured by a virtual reality street-crossing simulator (Aim 2). This will provide important ecologically valid data on the real world consequences of the sleep parameters examined. Finally, these findings will be translated to the home environment with a longer duration randomized evaluation of sleep-time LOW frequency STN DBS over one month (Aim 3). If this project is successful, the next step would be a larger-scale, multicenter study of sleep time LOW frequency stimulation. This could ultimately alter conventional methods of DBS programming, with different sleep and wake-time settings, to improve patient quality of life and safety. The PI is well positioned to implement the proposed studies and develop into an independent investigator. During pursuit of combined MD and PhD degrees, she developed an understanding of how to critically approach a research question, demonstrating success through publication of 3 first-author manuscripts (16-18). Her subsequent clinical residency training in neurology and fellowship training in both Movement Disorders and Sleep Medicine provide a framework upon which this proposal and her career can grow. The candidate's potential for contribution to this field of study has been recognized through receipt of peer-reviewed extramural funding and through publications in this area (15, 19). The PI's training to date demonstrates her dedication to a career in clinical science and patient-oriented research. The University of Alabama at Birmingham is the ideal environment for this proposed research. UAB ranks 20th for NIH funding and has one of the largest Divisions of Movement Disorders in the nation. The primary mentor for this proposal, David Standard, MD, PhD, is a leader in the field of Parkinson's disease research. The co-mentor, Susan Harding, MD, is a recognized expert in Sleep Medicine. Additional members of the mentoring team include David Rye, MD, PhD, an expert in Movement Disorders and Sleep Medicine at Emory University, and Gary Cutter, PhD, a specialist in biostatistics and clinical trial design. The necessary resources for implementation of this trial are available at UAB, including a large pool of patients (>700) with DBS from Which research participants can be drawn? Additionally, the UAB Sleep/Wake Disorders Center performs more than 2000 sleep studies per year and has 2 beds that are dedicated to research. Also, the virtual reality street crossing simulator was developed by David Scheele, PhD at UAB, and has the necessary infrastructure in place. UAB has coursework in biostatistics, trial design, and research ethics. Finally, UAB is a recipient of the NIH Clinical and Translational Science Award (CTSA) Program, providing resources for research, collaboration, education, and training through the UAB Center for Clinical and Translational Services. Successful funding and implementation of this trial will allow the PI to pursue her long-term career goals: 1) To gain recognition as an expert in the overlapping fields of Movement Disorders and Sleep Medicine, while helping to shape the clinical and research trajectory of these fields, 2) To determine the effects of sleep dysfunction and its treatment on motor symptoms in PD patients, and 3) To obtain consistent R01 funding as an independent physician scientist. In order to achieve these long-term goals, more immediate goals include: 1) To further develop an understanding of biostatistics and clinical trial design, 2) To obtain additional training in deep brain stimulator programming and the mechanisms of DBS, and 3) To develop and utilize virtual reality as a measure of safety outcomes related to sleep dysfunction in patients with PD. These short-term goals will be achieved through formal coursework, mentor-guided readings and discussions, and hands-on experience during implementation of the trial. The candidate's background and goals, the research and mentoring environment, and the design of the proposed study, which addresses multiple goals outlined in the NIH Parkinson's Disease Research Plan, positions the PI as an ideal candidate for the K23 mechanism.

Public Health Relevance

Sleep dysfunction is a common and disabling symptom that adversely affects quality of life in patients with Parkinson's disease (PD). The proposed research will test the effects of low frequency deep brain stimulation (DBS) of the sub thalamic nucleus (STN) on sleep and vigilance in patients with PD. This trial could ultimately alter methods of DBS programming, with different sleep- and wake-time settings, to improve patient quality of life and Public safety.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Mentored Patient-Oriented Research Career Development Award (K23)
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NST-1 Subcommittee (NST-1)
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Sieber, Beth-Anne
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University of Alabama Birmingham
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Amara, Amy W; Memon, Adeel A (2018) Effects of Exercise on Non-motor Symptoms in Parkinson's Disease. Clin Ther 40:8-15
Amara, Amy W; Chahine, Lana M; Videnovic, Aleksandar (2017) Treatment of Sleep Dysfunction in Parkinson's Disease. Curr Treat Options Neurol 19:26
Ford, Kristin J; Joop, Allen; Memon, Raima A et al. (2017) Pedestrian safety in patients with Parkinson's disease: A case-control study. Mov Disord 32:1748-1755
Birchall, Elizabeth L; Walker, Harrison C; Cutter, Gary et al. (2017) The effect of unilateral subthalamic nucleus deep brain stimulation on depression in Parkinson's disease. Brain Stimul 10:651-656
Kelly, Neil A; Wood, Kimberly H; Allendorfer, Jane B et al. (2017) High-Intensity Exercise Acutely Increases Substantia Nigra and Prefrontal Brain Activity in Parkinson's Disease. Med Sci Monit 23:6064-6071
Amara, Amy W; Walker, Harrison C; Joop, Allen et al. (2017) Effects of subthalamic nucleus deep brain stimulation on objective sleep outcomes in Parkinson's disease. Mov Disord Clin Pract 4:183-190
Chahine, Lama M; Amara, Amy W; Videnovic, Aleksandar (2017) A systematic review of the literature on disorders of sleep and wakefulness in Parkinson's disease from 2005 to 2015. Sleep Med Rev 35:33-50
Amara, Amy W; Chahine, Lama M; Caspell-Garcia, Chelsea et al. (2017) Longitudinal assessment of excessive daytime sleepiness in early Parkinson's disease. J Neurol Neurosurg Psychiatry 88:653-662
Litvan, Irene; Lees, Peter S J; Cunningham, Christopher R et al. (2016) Environmental and occupational risk factors for progressive supranuclear palsy: Case-control study. Mov Disord 31:644-52
Chahine, L M; Xie, S X; Simuni, T et al. (2016) Longitudinal changes in cognition in early Parkinson's disease patients with REM sleep behavior disorder. Parkinsonism Relat Disord 27:102-6

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