Optical vagus nerve modulation of heart and respiration via heart-injected retrograde AAV

AbstractVagus nerve stimulation has shown many benefits for disease therapies but current approaches involve imprecise electrical stimulation that gives rise to off-target effects, while the functionally relevant pathways remain poorly understood. One method to overcome these limitations is the use of optogenetic techniques, which facilitate targeted neural communication with light-sensitive actuators (opsins) and can be targeted to organs of interest based on the location of viral delivery. Here, we tested whether retrograde adeno-associated virus (rAAV2-retro) injected in the heart can be used to selectively express opsins in vagus nerve fibers controlling cardiac function. Furthermore, we investigated whether perturbations in cardiac function could be achieved with photostimulation at the cervical vagus nerve. Viral injection in the heart resulted in robust, primarily afferent, opsin reporter expression in the vagus nerve, nodose ganglion, and brainstem. Photostimulation using both one-photon stimulation and two-photon holography with a GRIN-lens incorporated nerve cuff, was tested on the pilot-cohort of injected mice. Changes in heart rate, surface electrocardiogram, and respiratory responses were observed in response to both one- and two-photon photostimulation. The results demonstrate feasibility of retrograde labeling for organ targeted optical neuromodulation.

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Selective Modulation of Heart and Respiration by Optical Control of Vagus Nerve Axons Innervating the Heart

10.1101/2020.06.26.173898 ◽

2020 ◽

Author(s):

Arjun K. Fontaine ◽

Gregory L. Futia ◽

Pradeep S. Rajendran ◽

Samuel Littich ◽

Naoko Mizoguchi ◽

...

Keyword(s):

Vagus Nerve ◽

Vagus Nerve Stimulation ◽

Optical Control ◽

Reporter Expression ◽

Adeno Associated Virus ◽

Therapeutic Benefits ◽

Neural Communication ◽

Selective Modulation ◽

Control Of Expression ◽

Respiratory Responses

AbstractTargeting specifics subsets of peripheral pathways of the autonomic nervous system will enable new avenues to study organ control and develop new disease therapies. Vagus nerve stimulation (VNS) has shown many therapeutic benefits but current approaches involve imprecise electrical stimulation that gives rise to adverse effects, and the functionally relevant pathways are poorly understood. One method to overcome these limitations is the use of optogenetic techniques, which facilitate highly specific neural communication with light-sensitive actuators (opsins). Opsins can be targeted to cell populations of interest based on the location of viral delivery and genetic control of expression. Here, we tested whether holographic photostimulation of subsets of axons of the cervical vagus nerve that innervate the heart can be used to modulate cardiac function. Viral injection of retrograde adeno-associated virus (rAAV2-retro) in the heart resulted in robust, primarily afferent, opsin reporter expression in the vagus nerve, nodose ganglion, and brainstem. Selective holographic photostimulation of axons resulted in changes in heart rate, surface cardiac electrogram, and respiratory responses that were different from responses elicited by whole nerve photostimulation.

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Selective stimulation of the ferret abdominal vagus nerve with multi-contact nerve cuff electrodes

Scientific Reports ◽

10.1038/s41598-021-91900-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jonathan A. Shulgach ◽

Dylan W. Beam ◽

Ameya C. Nanivadekar ◽

Derek M. Miller ◽

Stephanie Fulton ◽

...

Keyword(s):

Vagus Nerve ◽

Nerve Fibers ◽

The Body ◽

Evoked Responses ◽

Gi Tract ◽

Selective Stimulation ◽

Nerve Cuff ◽

Cuff Electrodes ◽

Nerve Cuff Electrodes ◽

Stimulation Of

AbstractDysfunction and diseases of the gastrointestinal (GI) tract are a major driver of medical care. The vagus nerve innervates and controls multiple organs of the GI tract and vagus nerve stimulation (VNS) could provide a means for affecting GI function and treating disease. However, the vagus nerve also innervates many other organs throughout the body, and off-target effects of VNS could cause major side effects such as changes in blood pressure. In this study, we aimed to achieve selective stimulation of populations of vagal afferents using a multi-contact cuff electrode wrapped around the abdominal trunks of the vagus nerve. Four-contact nerve cuff electrodes were implanted around the dorsal (N = 3) or ventral (N = 3) abdominal vagus nerve in six ferrets, and the response to stimulation was measured via a 32-channel microelectrode array (MEA) inserted into the left or right nodose ganglion. Selectivity was characterized by the ability to evoke responses in MEA channels through one bipolar pair of cuff contacts but not through the other bipolar pair. We demonstrated that it was possible to selectively activate subpopulations of vagal neurons using abdominal VNS. Additionally, we quantified the conduction velocity of evoked responses to determine what types of nerve fibers (i.e., Aδ vs. C) responded to stimulation. We also quantified the spatial organization of evoked responses in the nodose MEA to determine if there is somatotopic organization of the neurons in that ganglion. Finally, we demonstrated in a separate set of three ferrets that stimulation of the abdominal vagus via a four-contact cuff could selectively alter gastric myoelectric activity, suggesting that abdominal VNS can potentially be used to control GI function.

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In vivo holographic photo-stimulation and two photon GCaMP6 imaging of vagus nerve axons using a GRIN lens integrated nerve cuff

Optogenetics and Optical Manipulation 2019 ◽

10.1117/12.2521830 ◽

2019 ◽

Cited By ~ 1

Author(s):

Gregory L. Futia ◽

Arjun Fontaine ◽

Samuel Littich ◽

Connor McCullough ◽

Diego Restrepo ◽

...

Keyword(s):

Vagus Nerve ◽

Two Photon ◽

Grin Lens ◽

Nerve Cuff

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Selective stimulation of the ferret abdominal vagus nerve with multi-contact nerve cuff electrodes

10.1101/2021.02.19.431879 ◽

2021 ◽

Author(s):

Jonathan A. Shulgach ◽

Dylan W. Beam ◽

Ameya C. Nanivadekar ◽

Derek M. Miller ◽

Stephanie Fulton ◽

...

Keyword(s):

Vagus Nerve ◽

Nerve Fibers ◽

Vagal Afferents ◽

Evoked Responses ◽

Gi Tract ◽

Selective Stimulation ◽

Nerve Cuff ◽

Cuff Electrodes ◽

Nerve Cuff Electrodes ◽

Stimulation Of

AbstractDysfunction and diseases of the gastrointestinal (GI) tract are a major driver of medical care. The vagus nerve innervates and controls multiple organs of the GI tract and vagus nerve stimulation (VNS) could provide a means for affecting GI function and treating disease. However, the vagus nerve also innervates many other organs throughout the body, and off-target effects of VNS could cause major side effects such as changes in blood pressure. In this study, we aimed to achieve selective stimulation of populations of vagal afferents using a multi-contact cuff electrode wrapped around the abdominal trunks of the vagus nerve. Four-contact nerve cuff electrodes were implanted around the dorsal (N=3) or ventral (N=3) abdominal vagus nerve in six ferrets, and the response to stimulation was measured via a 32-channel microelectrode array (MEA) inserted into the nodose ganglion. Selectivity was characterized by the ability to evoke responses in MEA channels through one bipolar pair of cuff contacts but not through the other bipolar pair. We demonstrated that is was possible to selectively activate subpopulations of vagal afferents using abdominal VNS. Additionally, we quantified the conduction velocity of evoked responses to determine what types of nerve fibers (i.e. Aδ vs. C) responded to stimulation. We also quantified the spatial organization of evoked responses in the nodose MEA to determine if there is somatotopic organization of the neurons in that ganglion. Finally, we demonstrated in a separate set of three ferrets that stimulation of the abdominal vagus via a four-contact cuff could selectively alter gastric myoelectric activity, suggesting that abdominal VNS can potentially be used to control GI function.

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Sources of Off-Target Effects of Vagus Nerve Stimulation Using the Helical Clinical Lead in Domestic Pigs

10.1101/2020.01.15.907246 ◽

2020 ◽

Author(s):

Evan N. Nicolai ◽

Megan L. Settell ◽

Bruce E. Knudsen ◽

Andrea L. McConico ◽

Brian A. Gosink ◽

...

Keyword(s):

Side Effects ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Muscle Activation ◽

Motor Nerve ◽

Nerve Fibers ◽

Large Animal ◽

C Fibers ◽

Target Effects

AbstractClinical data suggest that efficacious vagus nerve stimulation (VNS) is limited by side effects such as cough and dyspnea that have stimulation thresholds lower than those for therapeutic outcomes. VNS side effects are putatively caused by activation of nearby muscles within the neck, via direct muscle activation or activation of nerve fibers innervating those muscles. Our goal was to determine the thresholds at which various VNS-evoked effects occur in the domestic pig—an animal model with vagus anatomy similar to human—using the bipolar helical lead deployed clinically. Intrafascicular electrodes were placed within the vagus nerve to record electroneurographic (ENG) responses, and needle electrodes were placed in the vagal-innervated neck muscles to record electromyographic (EMG) responses. Contraction of the cricoarytenoid muscle occurred at low amplitudes (∼0.3 mA) and resulted from activation of motor nerve fibers in the cervical vagus trunk within the electrode cuff which bifurcate into the recurrent laryngeal branch of the vagus. At higher amplitudes (∼1.4 mA), contraction of the cricoarytenoid and cricothyroid muscles was generated by current leakage outside the cuff to activate motor nerve fibers running within the nearby superior laryngeal branch of the vagus. Activation of these muscles generated artifacts in the ENG recordings that may be mistaken for compound action potentials representing slowly conducting Aδ-, B-, and C-fibers. Our data resolve conflicting reports of the stimulation amplitudes required for C-fiber activation in large animal studies (>10 mA) and human studies (<250 µA). After removing muscle-generated artifacts, ENG signals with post-stimulus latencies consistent with Aδ- and B-fibers occurred in only a small subset of animals, and these signals had similar thresholds to those that caused bradycardia. By identifying specific neuroanatomical pathways that cause off-target effects and characterizing the stimulation dose-response curves for on- and off-target effects, we hope to guide interpretation and optimization of clinical VNS.

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Effect of defibrillation on the performance of an implantable vagus nerve stimulation system

Bioelectronic Medicine ◽

10.1186/s42234-021-00064-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Imad Libbus ◽

Scott R. Stubbs ◽

Scott T. Mazar ◽

Scott Mindrebo ◽

Bruce H. KenKnight ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Function ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Pulse Generator ◽

High Energy ◽

Implantable Pulse Generator ◽

Defibrillation Pulse ◽

Stimulation System

Abstract Background Vagus Nerve Stimulation (VNS) delivers Autonomic Regulation Therapy (ART) for heart failure (HF), and has been associated with improvement in cardiac function and heart failure symptoms. VNS is delivered using an implantable pulse generator (IPG) and lead with electrodes placed around the cervical vagus nerve. Because HF patients may receive concomitant cardiac defibrillation therapy, testing was conducted to determine the effect of defibrillation (DF) on the VNS system. Methods DF testing was conducted on three ART IPGs (LivaNova USA, Inc.) according to international standard ISO14708-1, which evaluated whether DF had any permanent effects on the system. Each IPG was connected to a defibrillation pulse generator and subjected to a series of high-energy pulses. Results The specified series of pulses were successfully delivered to each of the three devices. All three IPGs passed factory electrical tests, and interrogation confirmed that software and data were unchanged from the pre-programmed values. No shifts in parameters or failures were observed. Conclusions Implantable VNS systems were tested for immunity to defibrillation, and were found to be unaffected by a series of high-energy defibrillation pulses. These results suggest that this VNS system can be used safely and continue to function after patients have been defibrillated.

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Endings of the vagus nerve fibers in the mammalian heart

Kazan medical journal ◽

10.17816/kazmj77089 ◽

1927 ◽

Vol 23 (6-7) ◽

pp. 622-623

Author(s):

B. I. Lavrent'ev

Keyword(s):

Methylene Blue ◽

Vagus Nerve ◽

Nerve Fibers ◽

Nerve Cells ◽

Vagus Nerves ◽

Mammalian Heart ◽

Cardiac Ganglia ◽

Important Study ◽

Spiral Fibers

In 1893, Prof. V.V. Nikolaev, having cut vagus nerves of a frog, saw under a microscope degeneration of so-called spiral fibers and pericellular apparatuses on nerve cells of intracardiac nodes. Later these observations were thoroughly verified by Prof. D.V. Polumordvinov and fully confirmed by him. I had a chance to look through amazing by technique preparations of the late Prof. Polumordvinov, obtained by methylene blue method, on which decay of pericellular apparatuses in cardiac ganglia of a frog was absolutely clearly visible. D. V-ch, who died untimely in 1919, unfortunately, did not have time to publish in detail his important study; the manuscript and drawings of his work also remained undiscovered.

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Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers

Scientific Reports ◽

10.1038/s41598-021-99177-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Adam J. Davenport ◽

Ioana Neagoe ◽

Nico Bräuer ◽

Markus Koch ◽

Andrea Rotgeri ◽

...

Keyword(s):

Receptor Antagonist ◽

Underlying Disease ◽

Nerve Fibers ◽

P2x3 Receptor ◽

P2x3 Receptors ◽

Pain Pathways ◽

Pathological Pain ◽

Target Effects

AbstractATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.

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Barbiturates depress vagal motor pathway to ferret trachea at ganglia

Journal of Applied Physiology ◽

10.1152/jappl.1982.53.1.253 ◽

1982 ◽

Vol 53 (1) ◽

pp. 253-257 ◽

Cited By ~ 23

Author(s):

B. E. Skoogh ◽

M. J. Holtzman ◽

J. R. Sheller ◽

J. A. Nadel

Keyword(s):

Neuromuscular Junction ◽

Vagus Nerve ◽

Muscle Tension ◽

Postsynaptic Membrane ◽

Nerve Fibers ◽

Motor Pathway ◽

Parasympathetic Ganglia ◽

Before And After ◽

Nerve Muscle

To determine which site in the vagal motor pathway to airway smooth muscle is most sensitive to depression by barbiturates, we recorded isometric muscle tension in vitro and stimulated the vagal motor pathway at four different sites before and after exposure to barbiturates. In isolated tracheal rings from ferrets, we stimulated muscarinic receptors in the neuromuscular junction by exogenous acetylcholine, postganglionic nerve fibers by electrical fluid stimulation, and the postsynaptic membrane in ganglia by 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP). We also developed a tracheal nerve-muscle preparation to stimulate preganglionic fibers in the vagus nerve electrically. Activation of ganglia by DMPP or by vagus nerve stimulation was depressed by barbiturates at 10-fold lower concentrations than those depressing the activation of postganglionic nerves or the neuromuscular junction. These findings suggest that the postsynaptic membrane in parasympathetic ganglia is the site in the vagal motor pathway most sensitive to depression by barbiturates.

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Central-peripheral neural network interactions evoked by vagus nerve stimulation: functional consequences on control of cardiac function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00557.2015 ◽

2015 ◽

Vol 309 (10) ◽

pp. H1740-H1752 ◽

Cited By ~ 69

Author(s):

Jeffrey L. Ardell ◽

Pradeep S. Rajendran ◽

Heath A. Nier ◽

Bruce H. KenKnight ◽

J. Andrew Armour

Keyword(s):

Cardiac Function ◽

Vagus Nerve ◽

Nerve Stimulation ◽

Vagus Nerve Stimulation ◽

Vagal Afferents ◽

Intact State ◽

Mediated Effects ◽

Functional Consequences ◽

Anesthetized Dogs ◽

The Right

Using vagus nerve stimulation (VNS), we sought to determine the contribution of vagal afferents to efferent control of cardiac function. In anesthetized dogs, the right and left cervical vagosympathetic trunks were stimulated in the intact state, following ipsilateral or contralateral vagus nerve transection (VNTx), and then following bilateral VNTx. Stimulations were performed at currents from 0.25 to 4.0 mA, frequencies from 2 to 30 Hz, and a 500-μs pulse width. Right or left VNS evoked significantly greater current- and frequency-dependent suppression of chronotropic, inotropic, and lusitropic function subsequent to sequential VNTx. Bradycardia threshold was defined as the current first required for a 5% decrease in heart rate. The threshold for the right vs. left vagus-induced bradycardia in the intact state (2.91 ± 0.18 and 3.47 ± 0.20 mA, respectively) decreased significantly with right VNTx (1.69 ± 0.17 mA for right and 3.04 ± 0.27 mA for left) and decreased further following bilateral VNTx (1.29 ± 0.16 mA for right and 1.74 ± 0.19 mA for left). Similar effects were observed following left VNTx. The thresholds for afferent-mediated effects on cardiac parameters were 0.62 ± 0.04 and 0.65 ± 0.06 mA with right and left VNS, respectively, and were reflected primarily as augmentation. Afferent-mediated tachycardias were maintained following β-blockade but were eliminated by VNTx. The increased effectiveness and decrease in bradycardia threshold with sequential VNTx suggest that 1) vagal afferents inhibit centrally mediated parasympathetic efferent outflow and 2) the ipsilateral and contralateral vagi exert a substantial buffering capacity. The intact threshold reflects the interaction between multiple levels of the cardiac neural hierarchy.

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