Deep brain stimulation has revolutionized the treatment of PD and renewed the exploration of surgical therapy for a wide range of neurological disorders including tremor, dystonia, obsessive compulsive disorder, depression, Tourette syndrome, addiction, pain and epilepsy. Despite the widespread use of DBS, its mechanism of action remains unclear. Debate continues over whether the beneficial effects of DBS are directly related to inhibition, excitation, changes in pattern, or some other as yet undetermined effect on neuronal activity. Three major issues limit the interpretation of previous studies that have sought to address the mechanism of action of DBS: 1) examining the effects of DBS on neuronal activity where behavioral state cannot be assessed (e.g. brain slices or anesthetized animals), 2) monitoring the effects of DBS at the site of stimulation without examining the effect on brain regions to which the stimulated site projects, and 3) examining the effects of DBS only after stimulation has been discontinued due to the problems associated with electrical stimulation artifacts. The results from many of these studies have been contradictory, likely secondary to the variety of conditions under which the experiments have been conducted. In addition most of these studies do not assess the effect of stimulation on neuronal activity during movement, the state during which most of the therapeutic effect of DBS is directed nor do they address the changes in neuronal activity at a network level. To address these limitations we propose to examine the effect of therapeutic DBS in the STN and GPi in monkeys performing a reaching task, while simultaneously recording from multiple nodal points in the basal ganglia thalamocortical network. Neuronal activity will be assessed under four conditions;at rest and during movement with and without stimulation. This study will provide significant insight into the changes in network activities that underlie the therapeutic effect of GPi and STN DBS on parkinsonian motor signs.

Public Health Relevance

The goal of this study is to understand how electrical stimulation in the brain improves the motor symptoms associated with Parkinson's disease (PD). An animal model of PD will be used to study the effect of therapeutic deep brain stimulation on the electrical activity of different brain structures that are thought to function abnormally in PD. The areas stimulated will be the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi), two structures now used to treat idiopathic PD in patients. This study is unique because it will investigate neuronal activity during movement from many different brain structures at the same time;most previous work has only studied one neuron at a time during rest. By recording from many different brain structures simultaneously during movement we will begin to understand how these structures work together to produce movement, what goes wrong during PD, and how electrical stimulation changes brain activity to improve symptoms. The results of this study will provide the rationale to help develop better ways to stimulate currently targeted brain regions, identify new targets that may be more effective than current ones, and develop new technology that will allow us to optimize the therapeutic effect of DBS for the treatment of PD and other neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037019-13
Application #
8305579
Study Section
Special Emphasis Panel (ZRG1-CND-E (90))
Program Officer
Sieber, Beth-Anne
Project Start
2008-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
13
Fiscal Year
2012
Total Cost
$532,604
Indirect Cost
$179,886
Name
University of Minnesota Twin Cities
Department
Neurology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Zhang, Jianyu; Wang, Zhong I; Baker, Kenneth B et al. (2012) Effect of globus pallidus internus stimulation on neuronal activity in the pedunculopontine tegmental nucleus in the primate model of Parkinson's disease. Exp Neurol 233:575-80
Vitek, Jerrold L; Zhang, Jianyu; Hashimoto, Takao et al. (2012) External pallidal stimulation improves parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia thalamic network. Exp Neurol 233:581-6
Baker, Kenneth B; Zhang, Jianyu; Vitek, Jerrold L (2011) Pallidal stimulation: effect of pattern and rate on bradykinesia in the non-human primate model of Parkinson's disease. Exp Neurol 231:309-13
Xu, Weidong; Miocinovic, Svjetlana; Zhang, Jianyu et al. (2011) Dissociation of motor symptoms during deep brain stimulation of the subthalamic nucleus in the region of the internal capsule. Exp Neurol 228:294-7
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Johnson, Matthew D; Vitek, Jerrold L; McIntyre, Cameron C (2009) Pallidal stimulation that improves parkinsonian motor symptoms also modulates neuronal firing patterns in primary motor cortex in the MPTP-treated monkey. Exp Neurol 219:359-62
Lempka, Scott F; Miocinovic, Svjetlana; Johnson, Matthew D et al. (2009) In vivo impedance spectroscopy of deep brain stimulation electrodes. J Neural Eng 6:046001

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