Calibration of Thresholds for Functional Engagement of Vagal A, B and C Fiber Groups
            <i>In Vivo</i>

McAllen, Robin M.; Shafton, Anthony D; Bratton, Bradford O.; Trevaks, David; Furness, John B.

doi:10.2217/bem-2017-0001

Cited by 70 publications

(65 citation statements)

References 24 publications

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“…Given those limitations, a method to quantitatively estimate the level of fiber engagement by cervical VNS using physiological parameters that, ideally, can be registered noninvasively, would be of use in preclinical and clinical research, and eventually in the clinical practice of VNS. To the best of our knowledge, ours is the first study to establish such a quantitative estimation method, even though attempts have been made to relate B-fiber activity to changes in heart rate [37] and to qualitatively calibrate functional thresholds for vagal fiber engagement [38]. First, we examined the feasibility of predicting the level of activation of different fiber types using physiological variables with a univariate (linear and nonlinear) regression model.…”

Section: Discussionmentioning

confidence: 99%

Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers

et al. 2020

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Background: Cervical vagus nerve stimulation (VNS) is an emerging bioelectronic treatment for brain, metabolic, cardiovascular and immune disorders. Its desired and off-target effects are mediated by different nerve fiber populations and knowledge of their engagement could guide calibration and monitoring of VNS therapies. Objective: Stimulus-evoked compound action potentials (eCAPs) directly provide fiber engagement information but are currently not feasible in humans. A method to estimate fiber engagement through common, noninvasive physiological readouts could be used in place of eCAP measurements. Methods: In anesthetized rats, we recorded eCAPs while registering acute physiological response markers to VNS: cervical electromyography (EMG), changes in heart rate (DHR) and breathing interval (DBI). Quantitative models were established to capture the relationship between A-, Band C-fiber type activation and those markers, and to quantitatively estimate fiber activation from physiological markers and stimulation parameters. Results: In bivariate analyses, we found that EMG correlates with A-fiber, DHR with B-fiber and DBI with C-fiber activation, in agreement with known physiological functions of the vagus. We compiled multivariate models for quantitative estimation of fiber engagement from these markers and stimulation parameters. Finally, we compiled frequency gain models that allow estimation of fiber engagement at a wide range of VNS frequencies. Our models, after calibration in humans, could provide noninvasive estimation of fiber engagement in current and future therapeutic applications of VNS.

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Section: Discussionmentioning

confidence: 99%

Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers

et al. 2020

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“…We next sought to confirm these findings in vivo . To evaluate activation of vagus nerve fibers, we measured rapid stimulation-dependent reduction in oxygen saturation, a well-described biomarker of vagus nerve stimulation ascribed to activation of the Hering-Breuer reflex (32). Stimulation of vagal A-fibers, including the pulmonary stretch receptors, temporarily prevents inhalation and causes blood oxygen saturation to fall (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The cavity was kept full of saline at all times. To assess activation of the vagus nerve, blood oxygen saturation (SpO2) was recorded using a pulse-oximeter (Starr Life Sciences™, MouseOx Plus®) as previously described (32). Data was read into MATLAB® using a Starr Link Plus™ with the outputs connected to analog channels on the Arduino®.…”

Section: Methodsmentioning

confidence: 99%

Flat Electrode Contacts for Peripheral Nerve Stimulation

Bucksot

Wells

Rahebi

et al. 2019

Preprint

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11The majority of available systems for nerve stimulation use circumferential stimulation electrodes inside 12 an insulating cuff, which produce largely uniform current density within the nerve. Flat stimulation 13 electrodes that contact only one side of the nerve may provide advantages including simpler 14 implantation, ease of production, and more resistance to mechanical failure. However, it is possible that 15 the flat configuration will yield inefficient fiber recruitment due to a less uniform current distribution 16 within the nerve. Here we tested the hypothesis that flat electrodes will require higher current amplitude 17 to achieve effective stimulation than circumferential designs. Computational modeling and in vivo 18 experiments were performed to evaluate fiber recruitment in different nerves and different species using 19 a variety of electrode designs. Initial results demonstrated similar fiber recruitment in the rat vagus and 20 sciatic nerves with a standard circumferential cuff electrode and a cuff electrode modified to 21 approximate a flat configuration. Follow up experiments comparing true flat electrodes to 22 circumferential electrodes on the rabbit sciatic nerve confirmed that fiber recruitment was equivalent 23 between the two designs. These findings demonstrate that flat electrodes represent a viable design for 24 nerve stimulation that may provide advantages over the current circumferential designs for applications 25 in which the goal is uniform activation of the nerve. 26 3 27 4 49 greater resistance to mechanical failure, and reduce cost of production. However, this electrode 50 geometry provides contact with only a portion of the circumference of the nerve, which is likely to 51 produce non-uniform stimulation. This would yield increased activation of axons near the contacts and 52 reduced activation of distant axons. The resulting polarity would lead to a lower threshold and higher 53 point of saturation and thus a less steep recruitment curve. Whether the magnitude of this effect would 54 substantially influence efficacy is not known. A direct comparison of flat and circumferential cuff 55 electrodes is needed to determine if flat contacts represent a practical alternative for nerve stimulation.56 57 5 58 Materials and Methods 59 Computational Model 60 A 3D model was created in Comsol (COMSOL Multiphysics® Version 5.3) consisting of a nerve with a 61single fascicle, perineurium, epineurium, two platinum contacts, an insulating cuff, and ambient 62 medium, similar to previous studies (14,15). In a subset of models, a multi-fascicle nerve containing five 63 fascicles was used ( Fig. 9). The nerve had a diameter of either 0.9 mm for the rat sciatic, 0.4 mm for the 64 rat vagus, or 3 mm for the rabbit sciatic (16-18). Perineurium thickness was set to 3% of the fascicle 65 diameter (19). Epineurium thickness was set to 0.13 mm for the rat sciatic, 0.1 mm for the rat vagus, and 66 0.43 mm for the rabbit sciatic (20-22). To investigate the effect of nerve size, the rabbit sciatic mode...

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“…VNS chronically restores autonomic imbalance, possibly via re-setting vagal and non-vagal autonomic reflexes between the brain and periphery Coleridge 1984) including alterations in the breathing rhythm, bronchial mucus secretion, bronchoconstriction and cough (Undem and Kollarik 2005), and possibly changes in local bronchial and pulmonary neuroimmune and inflammatory reflexes, with unknown functional and clinical significance (Adriaensen and Timmermans 2011). However, activation of C-type fibers happens at much higher current intensities than those of B-type fibers (Heinbecker 1930) and can easily be avoided by calibration of VNS intensity (McAllen et al 2018).…”

Section: Challenges For a Bioelectronic Treatment Of Pulmonary Hypertmentioning

confidence: 99%

Pulmonary arterial hypertension: the case for a bioelectronic treatment

et al. 2019

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Pulmonary arterial hypertension (PAH) is a rare disease of unknown etiology that progresses to right ventricular failure. It has a complex pathophysiology, which involves an imbalance between vasoconstrictive and vasodilative processes in the pulmonary circulation, pulmonary vasoconstriction, vascular and right ventricular remodeling, systemic inflammation, and autonomic imbalance, with a reduced parasympathetic and increased sympathetic tone. Current pharmacological treatments for PAH include several classes of drugs that target signaling pathways in vascular biology and cardiovascular physiology, but they can have severe unwanted effects and they do not typically stop the progression of the disease. Pulmonary artery denervation has been tested clinically as a method to suppress sympathetic overactivation, however it is a nonspecific and irreversible intervention. Bioelectronic medicine, in particular vagus nerve stimulation (VNS), has been used in cardiovascular disorders like arrhythmias, heart failure and arterial hypertension and could, in principle, be tested as a treatment in PAH. VNS can produce pulmonary vasodilation and renormalize right ventricular function, via activation of pulmonary and cardiac vagal fibers. It can suppress systemic inflammation, via activation of fibers that innervate the spleen. Finally, VNS can gradually restore the balance between parasympathetic and sympathetic tone by regulating autonomic reflexes. Preclinical studies support the feasibility of using VNS in PAH. However, there are challenges with such an approach, arising from the need to affect a relatively small number of relevant vagal fibers, and the potential for unwanted cardiac and noncardiac effects of VNS in this sensitive patient population.

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Calibration of Thresholds for Functional Engagement of Vagal A, B and C Fiber Groups In Vivo

Cited by 70 publications

References 24 publications

Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers

Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers

Flat Electrode Contacts for Peripheral Nerve Stimulation

Pulmonary arterial hypertension: the case for a bioelectronic treatment

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