Action potential initiation, propagation, and cortical invasion in the hyperdirect pathway during subthalamic deep brain stimulation
Background: High frequency (∼130 Hz) deep brain stimulation (DBS) of the subthalamic region is an established clinical therapy for the treatment of late stage Parkinson's disease (PD). Direct modulation of the hyperdirect pathway, defined as cortical layer V pyramidal neurons that send an axon...
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doaj-5773f1d77c87423b87355e76b999ac112021-03-19T07:12:12ZengElsevierBrain Stimulation1935-861X2018-09-0111511401150Action potential initiation, propagation, and cortical invasion in the hyperdirect pathway during subthalamic deep brain stimulationRoss W. Anderson0AmirAli Farokhniaee1Kabilar Gunalan2Bryan Howell3Cameron C. McIntyre4Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USADepartment of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USADepartment of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USADepartment of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USACorresponding author. Department of Biomedical Engineering, Case Western Reserve University, 2103 Cornell Road, Rm 6224, Cleveland, OH, 44106, USA.; Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH, 44106, USABackground: High frequency (∼130 Hz) deep brain stimulation (DBS) of the subthalamic region is an established clinical therapy for the treatment of late stage Parkinson's disease (PD). Direct modulation of the hyperdirect pathway, defined as cortical layer V pyramidal neurons that send an axon collateral to the subthalamic nucleus (STN), has emerged as a possible component of the therapeutic mechanisms. However, numerous questions remain to be addressed on the basic biophysics of hyperdirect pathway stimulation. Objective: Quantify action potential (AP) initiation, propagation, and cortical invasion in hyperdirect neurons during subthalamic stimulation. Methods: We developed an anatomically and electrically detailed computational model of hyperdirect neuron stimulation with explicit representation of the stimulating electric field, axonal response, AP propagation, and synaptic transmission. Results: We found robust AP propagation throughout the complex axonal arbor of the hyperdirect neuron. Even at therapeutic DBS frequencies, stimulation induced APs could reach all of the intracortical axon terminals with ∼100% fidelity. The functional result of this high frequency axonal driving of the thousands of synaptic connections made by each directly stimulated hyperdirect neuron is a profound synaptic suppression that would effectively disconnect the neuron from the cortical circuitry. Conclusions: The synaptic suppression hypothesis integrates the fundamental biophysics of electrical stimulation, axonal transmission, and synaptic physiology to explain a generic mechanism of DBS.http://www.sciencedirect.com/science/article/pii/S1935861X18301554Corticofugal axonPyramidal neuronSubthalamic nucleus |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Ross W. Anderson AmirAli Farokhniaee Kabilar Gunalan Bryan Howell Cameron C. McIntyre |
spellingShingle |
Ross W. Anderson AmirAli Farokhniaee Kabilar Gunalan Bryan Howell Cameron C. McIntyre Action potential initiation, propagation, and cortical invasion in the hyperdirect pathway during subthalamic deep brain stimulation Brain Stimulation Corticofugal axon Pyramidal neuron Subthalamic nucleus |
author_facet |
Ross W. Anderson AmirAli Farokhniaee Kabilar Gunalan Bryan Howell Cameron C. McIntyre |
author_sort |
Ross W. Anderson |
title |
Action potential initiation, propagation, and cortical invasion in the hyperdirect pathway during subthalamic deep brain stimulation |
title_short |
Action potential initiation, propagation, and cortical invasion in the hyperdirect pathway during subthalamic deep brain stimulation |
title_full |
Action potential initiation, propagation, and cortical invasion in the hyperdirect pathway during subthalamic deep brain stimulation |
title_fullStr |
Action potential initiation, propagation, and cortical invasion in the hyperdirect pathway during subthalamic deep brain stimulation |
title_full_unstemmed |
Action potential initiation, propagation, and cortical invasion in the hyperdirect pathway during subthalamic deep brain stimulation |
title_sort |
action potential initiation, propagation, and cortical invasion in the hyperdirect pathway during subthalamic deep brain stimulation |
publisher |
Elsevier |
series |
Brain Stimulation |
issn |
1935-861X |
publishDate |
2018-09-01 |
description |
Background: High frequency (∼130 Hz) deep brain stimulation (DBS) of the subthalamic region is an established clinical therapy for the treatment of late stage Parkinson's disease (PD). Direct modulation of the hyperdirect pathway, defined as cortical layer V pyramidal neurons that send an axon collateral to the subthalamic nucleus (STN), has emerged as a possible component of the therapeutic mechanisms. However, numerous questions remain to be addressed on the basic biophysics of hyperdirect pathway stimulation. Objective: Quantify action potential (AP) initiation, propagation, and cortical invasion in hyperdirect neurons during subthalamic stimulation. Methods: We developed an anatomically and electrically detailed computational model of hyperdirect neuron stimulation with explicit representation of the stimulating electric field, axonal response, AP propagation, and synaptic transmission. Results: We found robust AP propagation throughout the complex axonal arbor of the hyperdirect neuron. Even at therapeutic DBS frequencies, stimulation induced APs could reach all of the intracortical axon terminals with ∼100% fidelity. The functional result of this high frequency axonal driving of the thousands of synaptic connections made by each directly stimulated hyperdirect neuron is a profound synaptic suppression that would effectively disconnect the neuron from the cortical circuitry. Conclusions: The synaptic suppression hypothesis integrates the fundamental biophysics of electrical stimulation, axonal transmission, and synaptic physiology to explain a generic mechanism of DBS. |
topic |
Corticofugal axon Pyramidal neuron Subthalamic nucleus |
url |
http://www.sciencedirect.com/science/article/pii/S1935861X18301554 |
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