Udall Center-University of Minnesota

Udall Center-University of Minnesota

 

Director: Jerrold L. Vitek, M.D., Ph.D.

Title: Circuit-based deep brain stimulation for Parkinson’s disease

Website: http://udall.umn.edu/

 

Central Theme

The central theme of the University of Minnesota Udall center is to develop novel, circuit based deep brain stimulation (DBS) therapies for Parkinson’s disease (PD). This will be accomplished through an enhanced understanding of the pathophysiological activity patterns in the basal ganglia that underlie individual PD motor signs and the effect of changes in the DBS parameter space and location (subthalamic nucleus, STN; external, GPe, and internal, GPi, segments of the globus pallidus) on PD dopa-responsive and dopa-resistant motor signs. Through this understanding we will develop novel subject-specific stimulation strategies that optimize the therapeutic effects of DBS for individual symptoms based on state-of- the-art high-field imaging, computational modeling, and electrophysiological recordings. These studies will provide critical new knowledge of basal ganglia physiology in PD, define alternative DBS targets and stimulation parameters for the treatment of medication refractory gait, and balance problems, and develop novel closed loop and coordinated reset paradigms for patients with PD based on the observed changes in synchronized oscillatory activity in the basal ganglia, i.e. circuit-based DBS therapies.


Center Structure

The Administrative Core is directed by Dr. Jerrold Vitek and oversees the three Projects, three additional Cores, and all outreach and career enhancement activities. The Biostatistics Core, led by Dr. Lynn Eberly, provides statistical support and data management across the Center. The Imaging Core, led by Dr. Noam Harel, supports all three Projects with high-field structural and functional MR imaging. The Clinical Core, led by Drs. Scott Cooper, Paul Tuite, and Erin Holker, supports Projects 1 and 2 and will provide longitudinal common data elements (CDEs) on a cohort of people with PD that undergo standard of care DBS at UMN. 

Project 1 (Drs. Jerrold Vitek and Greg Molnar) will characterize the pathophysiological basis underlying the disruption in movement associated with PD and use this information to refine current and develop alternative DBS strategies. Project 2 (Drs. Colum MacKinnon and Cameron McIntyre) will characterize the relative effects of stimulation in specific regions of the pallidum on parkinsonian motor signs including both levodopa-responsive (rigidity, bradykinesia and tremor) and levodopa-resistant (balance, gait, and freezing) motor features. Project 3 (Drs. Matt Johnson and Tay Netoff) will focus on advancing behavior-based response surface optimization of DBS therapy for PD.
 

Recent Advances

●    In Project 1, we collected and analyzed resting and movement-related local field potential oscillations using newly introduced directional DBS leads. Data was interpreted in the context of lead locations and segment orientations using co-registered 7-T MRI and CT scans (Imaging Core). Results support the hypothesis that optimal improvement in motor signs is location specific and localized to the sensorimotor territory of the implanted nucleus and corresponds to the site of maximal power in LFP activity in the 5-35Hz frequency rage. Project 1 data also provides compelling evidence for the use of local field potential (LFP) activity obtained peri-operatively for the development of local predictive stimulation models that may optimize patient benefits while reducing clinic time needed for programming.


●    In Project 2, we developed a method for closed-loop evaluation of arm rigidity (using a robotic manipulandum) and adjustment of DBS stimulation parameters (e.g. frequency) using a Bayesian optimization approach. 


●    In Project 3, we developed an orientation-selective stimulation approach using directional DBS leads to allow more robust activation of pathways underlying treatment without inducing side effects with stimulation. The approach is now being evaluated in vivo in the context of treating parkinsonian motor signs. 
 

Public Health Statement

The University of Minnesota (UMN) Udall Center is aimed at improving the lives of patients with Parkinson’s disease (PD) through development of novel deep brain stimulation therapies. To do so, we must have a better understanding of the changes in brain circuitry that occur in PD. This understanding is critical if we are to advance deep brain stimulation and other therapies for the treatment of PD. Conventional DBS approaches target two deep brain structures, the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi). These structures are intimately involved in the development of movement problems in PD. When activity in these structures is modulated with DBS, people with PD experience significant relief in motor signs, a reduction in medication and significant improvement in their quality of life. Improvement in the slowness (bradykinesia), stiffness (rigidity) and shaking (tremor), however, is not consistent across patients, and some symptoms (e.g., gait, postural instability and freezing) are often resistant to DBS therapy as it is currently practiced today.

The UMN Udall will develop novel DBS strategies based on our understanding of the changes in brain activity that occur in people with PD. This understanding will result from studies in both people with PD as well as established pre-clinical model of PD where unconventional DBS stimulation settings can be explored. These strategies will not only improve current DBS approaches through development of new stimulation paradigms, but also develop target locations and stimulation strategies to improve motor signs resistant to current medical and DBS approaches. The UMN Udall Center will also provide cutting-edge cross training opportunities and career enhancement resources to Center Investigators and trainees, who comprise the next generation of PD researchers. Finally, the UMN Udall Center is committed to outreach to the local patient community, developing a partnership with local support groups and foundations to enhance patient care. The Center is coordinating with the local chapters of the National Parkinson Foundation and the American Parkinson’s Disease Association to engage with local and regional underserved communities.


Budget End Date: 2021/05/31

NIH Grant Number: P50 NS098573