Non-monotonic kilohertz frequency neural block thresholds arise from amplitude- and frequency-dependent charge imbalance

Peña, Edgar Carlos Quispe; Pelot, Nicole A.; Grill, Warren M.

doi:10.1038/s41598-021-84503-3

Cited by 11 publications

(12 citation statements)

References 53 publications

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“…However, that might also transiently bring more C-fibers into their absolute refractory period, even for a very short time, so fewer C-fibers will be able to generate action potentials in response to the probing stimulus, thus leading to smaller C-fiber eCAPs. It has recently been reported that neural block threshold increases monotonically with increasing frequency between 10 and 300 kHz, when KES is symmetrical(24, 67). Even though we used symmetric KES, in both experimental and modeling studies, we found non-monotonically varying neural block thresholds for A- and B- fibers (Figure 4).…”

Section: Discussionmentioning

confidence: 98%

“…5A-C, S6). However, elicited APs during KES trains cannot be resolved using the eCAP method as activities from multiple fibers are asynchronous 66 , and therefore have to be estimated indirectly, via fiber-mediated physiological responses. Drops in HR, associated primarily with B-fiber activation, are minimal during KES (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Kilohertz-frequency electrical stimulation (KES) blocks nerve conduction (23)(24)(25)(26) and is used in the vagus nerve for treating obesity (27) and in somatic sensory nerves for treating pain (28,29), with an assumed mechanism of action that involves blocking of C-afferents. Using electrical and optogenetic stimulation, imaging, physiological and computational methods, we show here that KES of the vagus nerve can instead preferentially activate C-afferents while simultaneously blocking larger fibers, in a reliable and reversible manner.…”

Section: Introductionmentioning

confidence: 99%

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Intermittent KHz-frequency electrical stimulation selectively engages small unmyelinated vagal afferents

Chang

Ahmed

Jayaprakash

et al. 2021

Preprint

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Cervical vagus nerve stimulation (VNS) provides relatively minimally-invasive access to vagal fiber populations innervating most visceral organs, making it an attractive therapy candidate for various diseases. To maximize desired and minimize off-target effects, VNS should be delivered in a fiber-selective manner. We sought to select and optimize parameters that preferentially activate large, intermediate or small-size vagal fibers in 2 animal species, rats and mice. We manipulated stimulus waveform and frequency of short-duration (10-s) stimulus trains (SSTs) at different intensities and measured fiber-specific stimulus-elicited compound action potentials, corresponding cardiorespiratory vagally-mediated responses and neuronal expression of c-FOS in sensory and motor brainstem nuclei. We compiled selectivity indices from those measurements to determine optimal parameters for each fiber type. Large- and intermediate-size fibers are activated by SSTs of 30 Hz frequency, using short-square and long-square or quasi-trapezoidal pulses, respectively, at different optimal intensities for different animals. Small-size fibers are activated by SSTs of frequencies >8KH at high stimulus intensities; using a computational model of vagal fibers we find that sodium channels may underlie this effect. All findings were consistent between rats and mice. Our study provides a robust design and optimization framework for targeting vagal fiber populations for improved safety and efficacy of VNS therapies.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intermittent KHz-frequency electrical stimulation selectively engages small unmyelinated vagal afferents

Chang

Ahmed

Jayaprakash

et al. 2021

Preprint

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“…To justify our conclusions on the excitatory effect of kHz-FS we need to consider some problems characteristic to high-frequency electrical stimulation. First, it has been recognized, that some types of kHz-generating hardware can introduce an extraneous DC component of the stimulation current [31][32] . To eliminate the undesirable DC currents one could either use a filtering module 31 or continuously monitor and neutralize DC shifts on the stimulator output and stimulating electrodes.…”

Section: Discussionmentioning

confidence: 99%

Effect of Biphasic kHz Field Stimulation on CA1 Pyramidal Neurons in Slices

Karnup

Groat²,

Beckel³

et al. 2022

MRAJ

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Electrical stimulation in the kilohertz-frequency range has been successfully used for treatment of various neurological disorders. Nevertheless, the mechanisms underlying this stimulation are poorly understood. To study the effect of kilohertz-frequency electric fields on neuronal membrane biophysics we developed a reliable experimental method to measure responses of single neurons to kilohertz field stimulation in brain slice preparations. In the submerged brain slice pyramidal neurons of the CA1 subfield were recorded in the whole-cell configuration before, during and after stimulation with a biphasic charge balanced electric field at 2kHz, 5kHz or 10 kHz. The slice was placed in a 1 mm gap between two parallel 2 mm long platinum-iridium 0.1 mm diameter wire electrodes. Whole-cell recordings lasted for an hour or longer. Typically, a few 5-10 min long sessions of kHz-field stimulation (kHz-FS) with various frequency/amplitude combinations were applied to assess the type of neuronal response and possible changes of its membrane characteristics. It was found that kHz-field stimulation at all frequencies elicited reproducible excitatory neuronal responses lasting throughout stimulation period, but not after cessation of kHz-FS. During kHz-FS the rheobase usually decreased. In addition, spontaneous firing might be initiated in some silent neurons or became more intense in previously spontaneously active neurons. Response thresholds were in the range of 0.5-2 mA and were higher at higher frequencies. Blockade of glutamatergic synaptic transmission did not alter the magnitude of responses. Inhibitory synaptic input was not changed by kilohertz field stimulation. We conclude that kHz-frequency current applied in brain tissue has an excitatory effect on pyramidal neurons during stimulation. This effect is more prominent and occurs at a lower stimulus intensity at a frequency of 2kHz as compared to 5kHz and 10kHz.

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“…These extrapolations lead to errors which degrade the accuracy and the realism of the outcomes coming from the model.For example, Grinberg et al, 12 ran a meta‐analysis for the thickness of human perineurium versus fascicle diameter and found that this was 3% ± 1%. Later, this value was applied to the rat tibial model 13 with the assumption that the cross species and size scales were the same 3%. Another example exists for the temperature coefficient factor, Q 10 , which is used without direct or indirect validation outside its original context.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the electrical properties of mammalian peripheral nerve laminae

et al. 2023

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Background and Objective:The intrinsic electrical material properties of the laminar components of the mammalian peripheral nerve bundle are important parameters necessary for the accurate simulation of the electrical interaction between nerve fibers and neural interfaces. Improvements in the accuracy of these parameters improve the realism of the simulation and enables realistic screening of novel devices used for extracellular recording and stimulation of mammalian peripheral nerves. This work aims to characterize these properties for mammalian peripheral nerves to build upon the resistive parameter set established by Weerasuriya et al. in 1984 for amphibian somatic peripheral nerves (frog sciatic nerve) that is currently used ubiquitously in the in-silico peripheral nerve modeling community.Methods: A custom designed characterization chamber was implemented and used to measure the radial and longitudinal impedance between 10 mHz and 50 kHz of freshly excised canine vagus nerves using four-point impedance spectroscopy. The impedance spectra were parametrically fitted to an equivalent circuit model to decompose and estimate the components of the various laminae.Histological sections of the electrically characterized nerves were then made to quantify the geometry and laminae thicknesses of the perineurium and epineurium. These measured values were then used to calculate the estimated intrinsic electrical properties, resistivity and permittivity, from the decomposed resistances and reactances. Finally, the estimated intrinsic electrical properties were used in a finite element method (FEM) model of the nerve characterization setup to evaluate the realism of the model. Results:The geometric measurements were as follows: nerve bundle (1.6 ± 0.6 mm), major nerve fascicle diameter (1.3 ± 0.23 mm), and perineurium thickness (13.8 ± 2.1 μm). The longitudinal resistivity of the endoneurium was estimated to be 0.97 ± 0.05 Ωm. The relative permittivity and resistivity of the perineurium were estimated to be 2018 ± 391 and 3.75 kΩm ± 981 Ωm, respectively. The relative permittivity and resistivity of the epineurium were found to be 9.4 × 10 6 ± 8.2 × 10 6 and 55.0 ± 24.4 Ωm, respectively.

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Non-monotonic kilohertz frequency neural block thresholds arise from amplitude- and frequency-dependent charge imbalance

Cited by 11 publications

References 53 publications

Intermittent KHz-frequency electrical stimulation selectively engages small unmyelinated vagal afferents

Intermittent KHz-frequency electrical stimulation selectively engages small unmyelinated vagal afferents

Effect of Biphasic kHz Field Stimulation on CA1 Pyramidal Neurons in Slices

Characterization of the electrical properties of mammalian peripheral nerve laminae

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