Chronic high frequency electrical stimulation of the brain, called deep brain stimulation (DBS), has evolved from a highly experimental technique to a well-established therapy for the treatment of movement disorders including dystonia, essential tremor (ET), and Parkinson's disease (PD). While the clinical benefits of DBS are well documented, fundamental questions remain about the mechanisms of action. This lack of understanding will limit full development and optimization of this promising treatment. We propose to quantify the effects of temporally non-regular patterns of DBS (i.e., non-constant interpulse intervals) on neuronal activity and motor function across the spectrum of computational models, in vivo animal experiments, and persons with PD or ET. We will first confirm the hypothesis that the symptom reduction from DBS is dependent on the pattern of stimulation, rather than just the rate of stimulation. We expect that symptom relief by DBS will decrease as the stimulus train is made more irregular. Subsequently, we will we will quantify the effects of pauses, bursts, and irregularity in the stimulus train to probe the mechanisms for the ineffectiveness of irregular stimulation. Specific non-regular patterns of stimulation will enable testing of three hypotheses that explain why non-regular stimulation is less effective than regular stimulation. Finally, we will use model-based optimization to design, and subsequently test in animals and humans, novel non-regular stimulation patterns. These patterns are intended to produce symptom relief at a lower average frequency, and thereby reduce the intensity of side effects and increase stimulator battery life. The outcome of the proposed project will address the fundamental question of the effect of the temporal pattern of DBS on relief of motor symptoms and neuronal activity and thus improve greatly our understanding of mechanisms of action. This understanding will inform identification of more easily accessible anatomical locations to deliver DBS and establish a foundation upon which to build future applications of electrical stimulation in the brain.

Public Health Relevance

NARRATIVE: The clinical benefits of deep brain stimulation to treat movement disorders including dystonia, essential tremor, and Parkinson's disease are well established, but fundamental questions remain about the mechanisms of action. The outcome of the proposed project will determine the effects of the temporal patterns of deep brain stimulation on relief of motor symptoms and patterns of neuronal activity and thus enable the full development and optimization of this promising treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040894-09
Application #
8212362
Study Section
Special Emphasis Panel (ZRG1-ETTN-A (03))
Program Officer
Ludwig, Kip A
Project Start
2000-09-30
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
9
Fiscal Year
2012
Total Cost
$342,565
Indirect Cost
$101,116
Name
Duke University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Swan, Brandon D; Grill, Warren M; Turner, Dennis A (2014) Investigation of deep brain stimulation mechanisms during implantable pulse generator replacement surgery. Neuromodulation 17:419-24; discussion 424
Howell, Bryan; Naik, Sagar; Grill, Warren M (2014) Influences of interpolation error, electrode geometry, and the electrode-tissue interface on models of electric fields produced by deep brain stimulation. IEEE Trans Biomed Eng 61:297-307
Medina, Leonel E; Grill, Warren M (2014) Volume conductor model of transcutaneous electrical stimulation with kilohertz signals. J Neural Eng 11:066012
Howell, Bryan; Grill, Warren M (2014) Evaluation of high-perimeter electrode designs for deep brain stimulation. J Neural Eng 11:046026
Dorval, Alan D; Grill, Warren M (2014) Deep brain stimulation of the subthalamic nucleus reestablishes neuronal information transmission in the 6-OHDA rat model of parkinsonism. J Neurophysiol 111:1949-59
Birdno, Merrill J; Tang, Wei; Dostrovsky, Jonathan O et al. (2014) Response of human thalamic neurons to high-frequency stimulation. PLoS One 9:e96026
Brocker, David T; Swan, Brandon D; Turner, Dennis A et al. (2013) Improved efficacy of temporally non-regular deep brain stimulation in Parkinson's disease. Exp Neurol 239:60-7
Gross, Robert E; McDougal, Margaret E (2013) Technological advances in the surgical treatment of movement disorders. Curr Neurol Neurosci Rep 13:371
So, Rosa Q; Kent, Alexander R; Grill, Warren M (2012) Relative contributions of local cell and passing fiber activation and silencing to changes in thalamic fidelity during deep brain stimulation and lesioning: a computational modeling study. J Comput Neurosci 32:499-519
Birdno, Merrill J; Kuncel, Alexis M; Dorval, Alan D et al. (2012) Stimulus features underlying reduced tremor suppression with temporally patterned deep brain stimulation. J Neurophysiol 107:364-83

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