Deep brain stimulation (DBS) of the globus pallidus (GP) is an effective treatment for patients with advanced Parkinson's disease (PD). Despite recent successes, the precise site(s) within the pallidum and physiological mechanism(s) of the therapy remain uncertain due in part to our limited understanding of the neural response to DBS. We hypothesize that parkinsonian motor symptoms have therapeutically distinct targets within the GP. By identifying the mechanisms of GP-DBS, we can then develop new stimulation patterns and electrodes to selectively target the cell groups implicated in the therapeutic benefit while minimizing stimulation induced side-effects. In this study, we propose to develop anatomically and biophysically accurate models of DBS in the globus pallidus externus (GPe) and globus pallidus internus (GPi) for four MPTP-treated, hemi-parkinsonian rhesus macaques. Each animal has been or will be implanted with a monkey-scaled version of a clinical DBS lead such that the four electrode contacts span the sensorimotor regions of both GPe and GPi. The computational models will be applied retrospectively to determine the neural response during therapeutic and non-therapeutic DBS in two monkeys. Models developed in two additional monkeys will then be used to prospectively evaluate the effects of targeted stimulation of specific anatomical territories. Our working hypothesis is that direct stimulation of the posteroventral sensorimotor GPi will primarily improve rigidity and levodopa-induced dyskinesias, whereas targeted stimulation of the sensorimotor aspects of dorsal GPi and ventral GPe will primarily improve bradykinesia. If the results of this study support this hypothesis with both retrospective and prospective evaluation, it will provide two important contributions to the field: 1) substantiate the technique of using detailed computational models to guide DBS parameter selection, and more importantly 2) provide anatomical and electrical guidelines for the clinical programming of GP-DBS implants. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS061541-01A1
Application #
7486386
Study Section
Special Emphasis Panel (ZRG1-F01-Z (20))
Program Officer
Sieber, Beth-Anne
Project Start
2008-03-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
1
Fiscal Year
2008
Total Cost
$51,326
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Johnson, Matthew D; Zhang, Jianyu; Ghosh, Debabrata et al. (2012) Neural targets for relieving parkinsonian rigidity and bradykinesia with pallidal deep brain stimulation. J Neurophysiol 108:567-77
Lempka, Scott F; Johnson, Matthew D; Miocinovic, Svjetlana et al. (2010) Current-controlled deep brain stimulation reduces in vivo voltage fluctuations observed during voltage-controlled stimulation. Clin Neurophysiol 121:2128-33
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
Mera, Thomas O; Johnson, Matthew D; Rothe, Darrin et al. (2009) Objective quantification of arm rigidity in MPTP-treated primates. J Neurosci Methods 177:20-9
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
Johnson, Matthew D; Miocinovic, Svjetlana; McIntyre, Cameron C et al. (2008) Mechanisms and targets of deep brain stimulation in movement disorders. Neurotherapeutics 5:294-308
Johnson, Matthew D; McIntyre, Cameron C (2008) Quantifying the neural elements activated and inhibited by globus pallidus deep brain stimulation. J Neurophysiol 100:2549-63