Udall Center-University of Minnesota

Director: Jerrold L. Vitek, MD, PhD

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

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

Budget End Date: 5/31/2021

 

Central Theme

The central theme of this 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 UMN Udall Center is comprised of three Research Projects and three integrated Cores:

Project 1, Pathophysiology and DBS (Jerrold L. Vitek, MD, PhD) 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. Although DBS has been demonstrated to reduce motor signs and improve the quality of life for patients with PD, outcomes vary significantly among patients and for individual motor signs within patients. This project will examine the relationship between changes in synchronized neural activity and motor behavior directly in patients by leveraging opportunities afforded by intra-operative, microelectrode mapping of the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) during DBS surgical procedures. Aim 1 will identify the changes in oscillatory brain activity that are associated with abnormal movements through intraoperative recordings of neuronal (single and paired) and LFP activity during the performance of reaching and repetitive movement tasks. Aim 2 will further characterize the changes in oscillatory activity in response to pharmacological and DBS treatment that reduces motor signs in patients with externalized DBS leads. Aim 3 will evaluate the potential role of these oscillatory changes as pathophysiological biomarkers for use in adaptive, closed-loop DBS systems.

Project 2: Dopa-resistant motor signs and DBS (Colum MacKinnon, PhD) 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. There has been a resurgence of interest in selecting the globus pallidus (GP) as a target for high frequency deep brain stimulation (DBS) to treat the motor symptoms of Parkinson’s disease (PD). Yet, despite increased consideration of the pallidum as a target candidate, few centers implant the pallidum and in those that do there is marked variability in the motor response across patients. Most centers implanting GPi report that the levodopa dose typically remains high, and, like subthalamic DBS, is it often ineffective for levodopa-resistant motor features such as postural instability, gait disturbances and freezing of gait. Aims 1 and 2 of this project will be initiated this year and will explore the hypothesis that the motor effects of pallidal stimulation (prokinetic or akinetic) are critically dependent upon the location of stimulation, and pathways activated by stimulation. Aim 1 will develop patient-specific tractography and neurostimulation models (derived from 7T MRI) to estimate the regions and pathways activated by stimulation across contacts spanning the dorsal to ventral regions of the pallidum (external, GPe, and internal, GPi, segments of the globus pallidus). Aim 2 will use quantitative measures of bradykinesia, rigidity, tremor, gait, gait initiation and postural stability to compare the effects of stimulation targeting the ventral GPe, dorsal GPi or ventral GPi compared with clinically optimized stimulation.

Project 3: Behavioral-based optimization of DBS (Matt Johnson, PhD) will focus on advancing behavior-based response surface optimization of DBS therapy for PD. While high frequency DBS is an effective therapy for treating the majority of motor symptoms of Parkinson’s disease (PD), the degree to which DBS therapy alleviates each motor symptom often varies from individual to individual. Project 3 will investigate the physiological basis for this variance and investigate two novel approaches to minimize dose-response variability in animal models. We will initiate Aims 1 and 2 of the project this year with DBS implants targeting the subthalamic nucleus and the globus pallidus. Aim 1 will investigate the ability of narrow DBS pulse widths to extend the therapeutic window between alleviating parkinsonian motor signs and evoking motor side effects. This aim will further enhance our understanding of the functional relationships between DBS parameter settings and their resultant therapeutic effect sizes and wash-in/wash-out time constants on a subject-specific, pathway-specific basis. Aim 2 will develop a novel real-time, behavior-based optimization algorithm for automatic and efficient selection of DBS parameters that minimize the expression of individual parkinsonian motor signs.  During behavioral data collection, we will also begin recording unit-spike and local field potential activity in three primary output nuclei of the internal globus pallidus (GPi): thalamic subnuclei ventralis lateralis, pars oralis (VLo), and the centromedian nucleus (CM), and the pedunculopontine nucleus (PPN), a brainstem locomotor region.

The Administrative Core (Dr. Vitek) oversees the three Projects, three additional Cores, and all outreach and career enhancement activities. The Biostatistics Core (Lynn Eberly, PhD) provides statistical support and data management across the Center. The Imaging Core (Noam Harel, PhD) supports all three Projects with high-field structural and functional MR imaging. The Clinical Core (Paul Tuite, MD) 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. 

Ongoing research at the UMN Udall Center addresses several NINDS PD2014 research priorities, including:

  • Clinical Recommendation 2: Develop effective treatments and companion biomarkers for dopa-resistant features of PD. These features include both motor symptoms, particularly gait and balance problems such as freezing of gait, and non-motor symptoms, especially cognitive impairment, psychosis, and dysautonomia.
  • Basic Recommendation 3: Understand how different cell populations change in their coding properties, firing patterns, and neural circuit dynamics over time; how these changes relate to behavior and motor control; and how therapeutic interventions may affect such changes.
  • Basic Recommendation 6: Develop approaches to exploit direct access to the human brain in individuals with PD during neurosurgical procedures such as DBS, for example using non-invasive high resolution magnetic resonance imaging and positron emission tomography.
  • Basic Recommendation 9: Use a combination of sensor technologies and imaging to develop a more precise understanding of the neural circuit dynamics in PD to enable the development of next-generation therapeutic devices.

Publications from the University of Minnesota Udall Center

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 (DBS) 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 DBS 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 movement-related symptoms, 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., walking (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.

For further information: Udall@umn.edu