Theta burst subthalamic nucleus deep brain stimulation for cognitive and motor improvements in Parkinson's Disease - Lewy body dementia (LBD) is the second most common cause of dementia after Alzheimer’s disease. In particular, Parkinson’s Disease (PD) progression has been associated with LBD and cognitive decline in a number of cognitive domains including executive function, attention, processing speed, episodic memory, and visuospatial processing. The predominant clinical motor features of PD are bradykinesia, resting tremor, and muscular rigidity; however, the prevalence and severity of the nonmotor effects of PD have significant detrimental effects on quality of life. While conventional pharmacological and surgical treatments of PD are effective in improving motor symptoms of PD, they do not improve cognitive deficits and may even have long-term deleterious effects on verbal fluency and cognition. Chronic high frequency deep brain stimulation (DBS) in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) is efficacious for improving motor symptoms of PD. Current stimulation parameters are optimized for motor benefit, with frequencies in the high gamma (100-180 Hz) range. Interestingly, increased low frequency oscillations (i.e. theta rhythms (4-8 Hz)) have been implicated in a range of cognitive functions, including spatial and episodic learning and memory. There is growing evidence that low (theta) frequency STN stimulation preferentially improves executive function compared to standard-of-care gamma DBS (cDBS). Indeed, we have generated data in PD patients with STN DBS that indicate “on” theta stimulation improves hippocampal-based verbal fluency compared to “off” or “on” gamma stimulation. Unfortunately, low frequency (theta or beta; 5-30 Hz) stimulation is not beneficial for motor symptoms. However, recent advances in stimulation programming allows for theta burst stimulation, which integrates high frequency (gamma 50-200 Hz; trains of 5-25) bursts of stimulation repeated at theta (5-10 Hz) frequency intervals. This theta burst stimulation increases theta oscillation activity. Moreover, there is evidence that STN theta burst stimulation is not only safe, but also has comparable motor outcomes compared to conventional gamma frequency STN DBS. Overall Goal: In light of our recent findings that theta stimulation improves cognitive function in PD patients with STN DBS, we hypothesize that chronic theta burst stimulation will confer a long-term cognitive benefit while concomitantly maintaining the motor benefits of gamma stimulation. The proposed randomized double-blind phase 2 clinical trial will focus on determining if 1) short-term and 2) chronic theta burst STN stimulation will improve both cognitive and motor measures; and 3) determining if theta-burst DBS and cDBS result in differing acute and chronic functional brain connectivity. The interpretation of data from this research will improve understanding of the acute and chronic effects of theta burst DBS on cognition and motor function. If successful, this study has the potential to develop a novel STN stimulation paradigm to treat both motor and cognitive PD symptoms as well as understand the effects of theta burst DBS compared to gamma DBS on fMRI functional connectivity measures. As this study is aimed at modulating cognitive networks, the ultimate goal is to develop novel stimulation parameters to treat chronic cognitive dysfunction in PD dementia and more broadly Lewy body dementia. Moreover, data collected, and collaborations developed will lay the foundation for a definitive Phase 3 clinical trial utilizing theta-burst stimulation for cognition and motor symptom improvement.
