Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current

Yang, Fei; Anderson, Michael J.; He, Shaoqiu; Stephens, K; Zheng, Yu; Chen, Zhiyong; Raja, Srinivasa N.; Aplin, Felix; Guan, Yun; Fridman, Gene Y.

doi:10.1126/sciadv.aaq1438

Cited by 34 publications

(40 citation statements)

References 36 publications

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“…The authors' explanation for how this block could occur is that during cathodic DC application, the voltage gated sodium channels are held in their inactivated states, preventing AP propagation (Bhadra and Kilgore, 2004). This argument is further supported by the investigation of the peripheral afferent cathodic block (Yang et al, 2018).…”

Section: Electrical Stimulation—neuron Interactionmentioning

confidence: 76%

“…In support of prediction 5, ionic channel conductances during DC presentation appear to critically influence the neural response (Yang et al, 2018). This was indicated with a neural block experiment in which a cathodic block exhibited different thresholds on different neuronal fiber types, which could not be explained entirely via differences in fiber diameter.…”

Section: Electrical Stimulation—neuron Interactionmentioning

confidence: 85%

“…DC can suppress or completely block nociceptive fibers directly, in principle foregoing the need for indirect or alternative approaches for suppression of the target neurons (Bhadra and Kilgore, 2004; Vrabec et al, 2017). DC fields may also be able to better target the thin myelinated Aδ fibers and unmyelinated, small-diameter C fibers that are the primary transmitters of the nociceptive signal in the periphery (Yang et al, 2018).…”

Section: Potential Applications For DC Modulationmentioning

confidence: 99%

“…The other reason that DC neuromodulation has gained interest in recent years is that the field of neuromodulation has become refined sufficiently to be faced with new challenges that are more difficult to address using pulsatile waveforms. Because DC directly controls membrane potential, it can increase or decrease firing rate, altogether block neural activity, control AP propagation velocity, and modulate synaptic connectivity (Goldberg et al, 1984; Bikson et al, 2004; Vrabec et al, 2017; Strang et al, 2018; Yang et al, 2018). DC also appears to maintain the stochastic properties of AP inter-pulse intervals on each neuron (Goldberg et al, 1984), in contrast to conventional pulsatile stimulation for which an evoked AP in phase with the stimulation pulse is the intended effect.…”

Section: Introductionmentioning

confidence: 99%

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Implantable Direct Current Neural Modulation: Theory, Feasibility, and Efficacy

Aplin

Fridman

2019

Front. Neurosci.

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Implantable neuroprostheses such as cochlear implants, deep brain stimulators, spinal cord stimulators, and retinal implants use charge-balanced alternating current (AC) pulses to recover delivered charge and thus mitigate toxicity from electrochemical reactions occurring at the metal-tissue interface. At low pulse rates, these short duration pulses have the effect of evoking spikes in neural tissue in a phase-locked fashion. When the therapeutic goal is to suppress neural activity, implants typically work indirectly by delivering excitation to populations of neurons that then inhibit the target neurons, or by delivering very high pulse rates that suffer from a number of undesirable side effects. Direct current (DC) neural modulation is an alternative methodology that can directly modulate extracellular membrane potential. This neuromodulation paradigm can excite or inhibit neurons in a graded fashion while maintaining their stochastic firing patterns. DC can also sensitize or desensitize neurons to input. When applied to a population of neurons, DC can modulate synaptic connectivity. Because DC delivered to metal electrodes inherently violates safe charge injection criteria, its use has not been explored for practical applicability of DC-based neural implants. Recently, several new technologies and strategies have been proposed that address this safety criteria and deliver ionic-based direct current (iDC). This, along with the increased understanding of the mechanisms behind the transcutaneous DC-based modulation of neural targets, has caused a resurgence of interest in the interaction between iDC and neural tissue both in the central and the peripheral nervous system. In this review we assess the feasibility of in-vivo iDC delivery as a form of neural modulation. We present the current understanding of DC/neural interaction. We explore the different design methodologies and technologies that attempt to safely deliver iDC to neural tissue and assess the scope of application for direct current modulation as a form of neuroprosthetic treatment in disease. Finally, we examine the safety implications of long duration iDC delivery. We conclude that DC-based neural implants are a promising new modulation technology that could benefit from further chronic safety assessments and a better understanding of the basic biological and biophysical mechanisms that underpin DC-mediated neural modulation.

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Section: Electrical Stimulation—neuron Interactionmentioning

confidence: 76%

Section: Electrical Stimulation—neuron Interactionmentioning

confidence: 85%

Section: Potential Applications For DC Modulationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Implantable Direct Current Neural Modulation: Theory, Feasibility, and Efficacy

Aplin

Fridman

2019

Front. Neurosci.

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“…Experimental data indicated that the Na v 1.1 and Na v 1.6 channels are preferentially expressed in the nodes of mammalian peripheral nerve fibers [49][50][51]. We substituted the HHtype models of I Naf and I Nap in node 6 to node 14 with the Markov-type models of Na v 1.1 and Na v 1.6 channels, respectively.…”

Section: Implementation Of Markov-type Vgscsmentioning

confidence: 99%

Kilohertz waveforms optimized to produce closed-state Na+ channel inactivation eliminate onset response in nerve conduction block

Grill

2020

PLoS Comput Biol

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The delivery of kilohertz frequency alternating current (KHFAC) generates rapid, controlled, and reversible conduction block in motor, sensory, and autonomic nerves, but causes transient activation of action potentials at the onset of the blocking current. We implemented a novel engineering optimization approach to design blocking waveforms that eliminated the onset response by moving voltage-gated Na + channels (VGSCs) to closed-state inactivation (CSI) without first opening. We used computational models and particle swarm optimization (PSO) to design a charge-balanced 10 kHz biphasic current waveform that produced conduction block without onset firing in peripheral axons at specific locations and with specific diameters. The results indicate that it is possible to achieve onset-free KHFAC nerve block by causing CSI of VGSCs. Our novel approach for designing blocking waveforms and the resulting waveform may have utility in clinical applications of conduction block of peripheral nerve hyperactivity, for example in pain and spasticity.

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Guide to Leveraging Conducting Polymers and Hydrogels for Direct Current Stimulation

Leal

Shaner

Matter

et al. 2023

Adv Materials Inter

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electronics), [1][2][3][4] solar cell technology, [5][6][7][8][9] solar water purification, [10] batteries (e.g., supercapacitors), [11][12][13][14] and biomedical engineering (e.g., electrode coating for recording and stimulation, drug delivery, scaffolds for tissue engineering). [15][16][17][18][19][20][21] The inherent conductivity of these polymers originates from their chemical structure consisting of repeating alternating chains of single and double (π-π) carbon bonds, allowing electrons to move freely alongside the polymeric backbone. Furthermore, these materials can be doped through several processes (e.g., chemically, electrochemically, photonically), effectively increasing their electrical conductivity through the buildup of polarons. [22] In addition to their outstanding and tunable electrical performance, CPs are a cost-effective alternative to metals, can be biodegradable and biocompatible, can be synthesized through a wide range of processes, and can be coated on different types of substrates. Amongst the most studied CPs, we find polypyrrole (PPy), polyaniline (PANI), and poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT/PSS). All these CPs have been extensively used in biomedical applications for bioelectrical measurements, electrical stimulation, drug delivery, and as bioactuators and biosensors. [23][24][25][26][27] Particularly, the use of PEDOT as a coating for stimulation electrodes has been at the center stage of research in the last decade due to the high electrochemical stability and three-dimensional structure of this polymer, The tunable electrical properties of conducting polymers (CPs), their biocompatibility, fabrication versatility, and cost-efficiency make them an ideal coating material for stimulation electrodes in biomedical applications. Several biological processes like wound healing, neuronal regrowth, and cancer metastasis, which rely on constant electric fields, demand electrodes capable of delivering direct current stimulation (DCs) for long times without developing toxic electrochemical reactions. Recently, CPs such as poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT/PSS) have demonstrated outstanding capability for delivering DCs without damaging cells in culture while not requiring intermediate buffers, contrary to the current research setups relying on noble-metals and buffering bridges. However, clear understanding of how electrode design and CP synthesis influence DCs properties of these materials has not been provided until now. This study demonstrates that various PEDOT-based CP coatings and hydrogels on rough electrodes can deliver DCs without substantial changes to the electrode and the noticeable development of chemical by-products depending on the electrode area and polymer thickness. A comprehensive analysis of the tested coatings is provided according to the desired application and available resources, alongside a proposed explanation for the observed electrochemical behavior. The CPs tested herein can pave the way toward the widespread...

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Differential expression of voltage-gated sodium channels in afferent neurons renders selective neural block by ionic direct current

Abstract: Researchers investigate the use of ionic direct current to reverse the standard neural stimulation recruitment order.

Cited by 34 publications

References 36 publications

Implantable Direct Current Neural Modulation: Theory, Feasibility, and Efficacy

Implantable Direct Current Neural Modulation: Theory, Feasibility, and Efficacy

Kilohertz waveforms optimized to produce closed-state Na+ channel inactivation eliminate onset response in nerve conduction block

Guide to Leveraging Conducting Polymers and Hydrogels for Direct Current Stimulation

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