The primary objectives of the proposed work are to determine what neural elements are activated by DBS, to develop methods to activate selectively local neurons and axons of passage, and to determine the motor effects) of stimulation of different neuronal groups. We will use computer-based modeling of thalamic neurons and the fields generated by DBS electrodes to determine the effects of stimulus parameters and electrode geometry variations on neuronal excitation and block. Hypotheses formulated from computer modeling will be tested. First, using paresthesias evoked by thalamic stimulation in awake human as a unique assay allowing Discrimination of activation of local or remote neural elements, and secondly by quantifying the motor effects:)f selective stimulation of local neurons and axons of passage. The outcomes of this research will be a thorough understanding of what neuronal elements (both type and spatial extent) are affected by DBS and methods to activate selectively targeted populations. We expect to design new stimulus waveforms and electrode geometries that will allow element- and location-specific; st1mulation of the human thalamus. These new techniques will enable us to define the populations of neurons that produce desired and undesired motor effects during DBS, and to specify the next generation of implantable electrodes and stimulators. Collectively, these results will improve the efficacy and expand the range of applications for DBS. Chronic high frequency electrical stimulation of the brain, also called deep brain stimulation,(CBD) is effective in treating a number of neurological disorders, but the mechanisms of action of unclear. A number of plausible hypotheses have been proposed, however, these hypotheses are difficult to support or refute because it is not known what neural elements (local cells, axons of passage) respond at similar stimulation thresholds. This lack of selectivity of the neural response complicates our understanding of the mechanisms of action of DBS, and limits our ability to maximally exploit DBS for therapy. However, if the responsive elements could be controlled selectively, then their differential effects may be used to expand the applications of DBS and minimize undesirable side effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS040894-01
Application #
6232624
Study Section
Special Emphasis Panel (ZNS1-SRB-K (01))
Program Officer
Sheehy, Paul A
Project Start
2000-09-30
Project End
2005-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
1
Fiscal Year
2000
Total Cost
$335,178
Indirect Cost
Name
Case Western Reserve University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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:
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
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
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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