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.

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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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ETTN-A (03))
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Ludwig, Kip A
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Duke University
Biomedical Engineering
Schools of Engineering
United States
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So, Rosa Q; McConnell, George C; Grill, Warren M (2017) Frequency-dependent, transient effects of subthalamic nucleus deep brain stimulation on methamphetamine-induced circling and neuronal activity in the hemiparkinsonian rat. Behav Brain Res 320:119-127
Brocker, David T; Swan, Brandon D; So, Rosa Q et al. (2017) Optimized temporal pattern of brain stimulation designed by computational evolution. Sci Transl Med 9:
Kumaravelu, Karthik; Brocker, David T; Grill, Warren M (2016) A biophysical model of the cortex-basal ganglia-thalamus network in the 6-OHDA lesioned rat model of Parkinson's disease. J Comput Neurosci 40:207-29
McConnell, George C; So, Rosa Q; Grill, Warren M (2016) Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation. J Neurophysiol 115:2791-802
Swan, Brandon D; Brocker, David T; Hilliard, Justin D et al. (2016) Short pauses in thalamic deep brain stimulation promote tremor and neuronal bursting. Clin Neurophysiol 127:1551-1559
Couto, João; Grill, Warren M (2016) Kilohertz Frequency Deep Brain Stimulation Is Ineffective at Regularizing the Firing of Model Thalamic Neurons. Front Comput Neurosci 10:22
Rossi, P Justin; Gunduz, Aysegul; Judy, Jack et al. (2016) Proceedings of the Third Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies. Front Neurosci 10:119
Grill, Warren M (2015) Model-based analysis and design of waveforms for efficient neural stimulation. Prog Brain Res 222:147-62
Howell, Bryan; Medina, Leonel E; Grill, Warren M (2015) Effects of frequency-dependent membrane capacitance on neural excitability. J Neural Eng 12:056015-56015
Howell, Bryan; Huynh, Brian; Grill, Warren M (2015) Design and in vivo evaluation of more efficient and selective deep brain stimulation electrodes. J Neural Eng 12:046030

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