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Journal ArticleDOI

Optimization of Transcutaneous Vagus Nerve Stimulation Using Functional MRI.

01 Apr 2017-Neuromodulation (Neuromodulation)-Vol. 20, Iss: 3, pp 290-300
TL;DR: In this article, the authors used functional magnetic resonance imaging (fMRI) to determine the most effective location for tVNS, and they found that stimulation at the ear canal resulted in the weakest activation of the solitary tract (NTS), the recipient of most afferent vagal projections, and a brainstem nucleus that receives direct input from the NTS.
Abstract: Objective/Hypothesis Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy, depression, and a number of other disorders. Transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) has been considered as a non-invasive alternative. Several functional magnetic resonance imaging (fMRI) studies on the effects of tVNS used different stimulation parameters and locations in the ear, which makes it difficult to determine the optimal tVNS methodology. The present study used fMRI to determine the most effective location for tVNS. Materials and Methods Four stimulation locations in the ear were compared: the inner tragus, inferoposterior wall of the ear canal, cymba conchae, and earlobe (sham). Thirty-seven healthy subjects underwent two 6-min tVNS stimulation runs per electrode location (monophasic rectangular 500 μs pulses, 25 Hz). General linear model was performed using SPM; region-of-interest analyses were performed for the brainstem areas. Results Stimulation at the ear canal resulted in the weakest activation of the nucleus of solitary tract (NTS), the recipient of most afferent vagal projections, and of the locus coeruleus (LC), a brainstem nucleus that receives direct input from the NTS. Stimulation of the inner tragus and cymba conchae activated these two nuclei as compared to sham. However, ROI analysis showed that only stimulation of the cymba conchae produced a significantly stronger activation in both the NTS and LC than did the sham stimulation. Conclusions These findings suggest that tVNS at the cymba conchae properly activates the vagal pathway and results in its strongest activation, and thus may be the optimal location for tVNS therapies applied to the auricle.
Citations
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Journal ArticleDOI
TL;DR: The neuroanatomy of the ABVN is explored with reference to clinical surveys examining Arnold’s reflex, cadaveric studies, fMRI studies, electrophysiological studies, acupuncture studies, retrograde tracing studies, and studies measuring changes in autonomic parameters in response to auricular tVNS.
Abstract: The array of end organ innervations of the vagus nerve, coupled with increased basic science evidence, has led to vagus nerve stimulation (VNS) being explored as a management option in a number of clinical disorders, such as heart failure, migraine and inflammatory bowel disease. Both invasive (surgically implanted) and non-invasive (transcutaneous) techniques of VNS exist. Transcutaneous VNS (tVNS) delivery systems rely on the cutaneous distribution of vagal afferents, either at the external ear (auricular branch of the vagus nerve) or at the neck (cervical branch of the vagus nerve), thus obviating the need for surgical implantation of a VNS delivery device and facilitating further investigations across a wide range of uses. The concept of electrically stimulating the auricular branch of the vagus nerve (ABVN), which provides somatosensory innervation to several aspects of the external ear, is relatively more recent compared with cervical VNS; thus, there is a relative paucity of literature surrounding its operation and functionality. Despite the increasing body of research exploring the therapeutic uses of auricular transcutaneous VNS (tVNS), a comprehensive review of the cutaneous, intracranial and central distribution of ABVN fibres has not been conducted to date. A review of the literature exploring the neuroanatomical basis of this neuromodulatory therapy is therefore timely. Our review article explores the neuroanatomy of the ABVN with reference to (1) clinical surveys examining Arnold's reflex, (2) cadaveric studies, (3) fMRI studies, (4) electrophysiological studies, (5) acupuncture studies, (6) retrograde tracing studies and (7) studies measuring changes in autonomic (cardiovascular) parameters in response to auricular tVNS. We also provide an overview of the fibre composition of the ABVN and the effects of auricular tVNS on the central nervous system. Cadaveric studies, of which a limited number exist in the literature, would be the 'gold-standard' approach to studying the cutaneous map of the ABVN; thus, there is a need for more such studies to be conducted. Functional magnetic resonance imaging (fMRI) represents a useful surrogate modality for discerning the auricular sites most likely innervated by the ABVN and the most promising locations for auricular tVNS. However, given the heterogeneity in the results of such investigations and the various limitations of using fMRI, the current literature lacks a clear consensus on the auricular sites that are most densely innervated by the ABVN and whether the brain regions secondarily activated by electrical auricular tVNS depend on specific parameters. At present, it is reasonable to surmise that the concha and inner tragus are suitable locations for vagal modulation. Given the therapeutic potential of auricular tVNS, there remains a need for the cutaneous map of the ABVN to be further refined and the effects of various stimulation parameters and stimulation sites to be determined.

180 citations


Cites background or methods from "Optimization of Transcutaneous Vagu..."

  • ...The earlobe has been widely used as a sham as it is thought to be relatively free of vagal afferents (Peuker & Filler, 2002; Yakunina et al. 2017) and innervated by the greater auricular nerve – a branch of the superficial cervical plexus....

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  • ...On the other hand, the same study showed that stimulation at the inner wall of the tragus and cymba concha successfully activated the vagal afferent pathway, with the greatest activation seen at the cymba concha, suggesting that this is the most promising site for auricular tVNS (Yakunina et al. 2017)....

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  • ...2018b) and cymba concha (Frangos et al. 2015; Yakunina et al. 2017; Wang et al. 2018) as active sites for vagal modulation, as supported by the cadaveric study conducted by Peuker & Filler (2002)....

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  • ...In one tVNS study, several regions of the limbic system were deactivated by both sham stimulation (applied at the earlobe) and tVNS (applied at the inner surface of the tragus, inferoposterior wall of the external acoustic meatus and cymba concha): namely, the hippocampus, the posterior cingulate gyrus, parahippocampal gyrus and amygdala (Yakunina et al. 2017)....

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  • ...Secondly, researchers should appreciate that stimulation of the earlobe is not physiologically inert and can produce very similar fMRI patterns to ABVN stimulation, although there is no substantial published evidence to date that the locus coeruleus and nucleus of the solitary tract (central vagal relay centres) are activated by electrical stimulation of the earlobe (Frangos et al. 2015; Yakunina et al. 2017)....

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Journal ArticleDOI
TL;DR: Stimulation of the tragus activates the cerebral afferents of the vagal pathway and combined with the review of the literature suggest that taVNS is a promising form of VNS.

170 citations

Journal ArticleDOI
TL;DR: Two reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aV NS technology to reach the patient.
Abstract: Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging technology in the field of bioelectronic medicine with applications in therapy. Modulation of the afferent vagus nerve affects a large number of physiological processes and bodily states associated with information transfer between the brain and body. These include disease mitigating effects and sustainable therapeutic applications ranging from chronic pain diseases, neurodegenerative and metabolic ailments to inflammatory and cardiovascular diseases. Given the current evidence from experimental research in animal and clinical studies we discuss basic aVNS mechanisms and their potential clinical effects. Collectively, we provide a focused review on the physiological role of the vagus nerve and formulate a biology-driven rationale for aVNS. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the framework of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on physiological aspects - a discussion of engineering aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.

157 citations


Cites background from "Optimization of Transcutaneous Vagu..."

  • ...Only the cymba concha was found so far to be solely innervated by aVN (Peuker and Filler, 2002) with the associated maximum activation of vagal projections in NTS during stimulation, as compared to tragus, cavum concha, or earlobe stimulation (Yakunina et al., 2016)....

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  • ...However, current imaging studies in humans are usually focused on VNactivated brain stem nuclei and their projections (Yakunina et al., 2016)....

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  • ..., 2007), whereas a significantly stronger activation of the NTS was proven when the cymba concha region was electrically stimulated in humans compared to sham stimulation and other auricular regions (Yakunina et al., 2016)....

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  • ...Auricular vagus nerve stimulation is typically performed at the tragus or (cavum, cymba) concha (Yakunina et al., 2016)....

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Journal ArticleDOI
TL;DR: VNS affects many of the same brain areas, neurotransmitters and signal transduction mechanisms as those found with traditional antidepressants, Nevertheless, the mechanisms by which VNS benefits patients nonresponsive to conventional antidepressants is unclear, with further research needed to clarify this.

128 citations

Journal ArticleDOI
TL;DR: It is found that transcutaneous auricular vagus nerve stimulation can significantly reduce multiple symptoms of depression patients, including anxiety, psychomotor retardation, sleep disturbance, and hopelessness.
Abstract: Depression is a highly prevalent disorder, and its treatment is far from satisfactory. There is an urgent need to develop a new treatment for depression. Although still at its early stage, transcutaneous auricular vagus nerve stimulation (taVNS) has shown promising potential for treating depression. In this article, we first summarize the results of clinical studies on the treatment effect of taVNS on depression. Then, we re-analyze a previous study to identify the specific symptoms taVNS can relieve as indicated by subscores of the 24-item Hamilton Depression Scale in patients with depression. We found that taVNS can significantly reduce multiple symptoms of depression patients, including anxiety, psychomotor retardation, sleep disturbance, and hopelessness. Next, we pose several hypotheses on the mechanism of taVNS treatment of depression, including directly and indirectly modulating the activity and connectivity of key brain regions involved in depression and mood regulation; inhibiting neuro-inflammatory sensitization; modulating hippocampal neurogenesis; and regulating the microbiome-brain-gut axis. Finally, we outline current challenges and lay out the future directions of taVNS treatment of depression, which include (1) intensively comparing stimulation parameters and "dose effect" (treatment frequency and duration) to maximize the treatment effect of taVNS; (2) exploring the effect of taVNS on disorders comorbid with depression (such as chronic pain disorders, cardiovascular disorder, and autism) to provide new "two-for-one" treatment approaches for patients with these disorders; and (3) applying multiple scale methods to explore the underlying mechanism of taVNS.

118 citations

References
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Journal ArticleDOI
03 Feb 2011-Nature
TL;DR: Evidence is reported that reversing the brain changes responsible can eliminate the perceptual impairment in an animal model of noise-induced tinnitus and this method for restoring neural activity to normal may be applicable to a variety of neurological disorders.
Abstract: Neuronal plasticity, the process by which the human brain changes as a result of experience, is thought to be the source of several chronic neurological conditions, including tinnitus. Using a rodent model for noise-induced tinnitus, Engineer et al. find that reversing neural plasticity induced by the tinnitus can correct perceptual impairment. Repeatedly pairing tones with a brief stimulation of the vagus nerve sharpens auditory neuron tuning and eliminates the physiological and behavioural signs of tinnitus. This proof of principle suggests that simply restoring normal neural activity to circuits that have been pathologically modified could provide a benefit in conditions involving aberrant neural plasticity. Neuronal plasticity is thought to be the source of several chronic neurological conditions, including tinnitus. Using a rodent model for noise-induced tinnitus, this study finds that reversing neural plasticity induced by the tinnitus can correct perceptual impairments caused by the ailment. Pairing tones with stimulation of the vagus nerve sharpened auditory neuron tuning and eliminated the physiological as well as behavioural correlates of the tinnitus. This proof of principle suggests that simply restoring normal neural activity to circuits that have been pathologically modified could provide a benefit in those ailments involving aberrant neural plasticity. Brain changes in response to nerve damage or cochlear trauma can generate pathological neural activity that is believed to be responsible for many types of chronic pain and tinnitus1,2,3. Several studies have reported that the severity of chronic pain and tinnitus is correlated with the degree of map reorganization in somatosensory and auditory cortex, respectively1,4. Direct electrical or transcranial magnetic stimulation of sensory cortex can temporarily disrupt these phantom sensations5. However, there is as yet no direct evidence for a causal role of plasticity in the generation of pain or tinnitus. Here we report evidence that reversing the brain changes responsible can eliminate the perceptual impairment in an animal model of noise-induced tinnitus. Exposure to intense noise degrades the frequency tuning of auditory cortex neurons and increases cortical synchronization. Repeatedly pairing tones with brief pulses of vagus nerve stimulation completely eliminated the physiological and behavioural correlates of tinnitus in noise-exposed rats. These improvements persisted for weeks after the end of therapy. This method for restoring neural activity to normal may be applicable to a variety of neurological disorders.

578 citations


"Optimization of Transcutaneous Vagu..." refers background in this paper

  • ...Recently, a rat model was used to demonstrate that VNS paired with tones reverses tinnitus-related plasticity of the auditory cortex (11)....

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Journal ArticleDOI
TL;DR: Although the precise mechanism of action of VNS is still unknown, the search for the mechanism has the potential to lend new insight into the neuropathology of depression, a review of the pre-clinical and clinical literature relating to VNS concludes.

568 citations

Journal ArticleDOI
TL;DR: The aim of this study was to describe the system of the auricular nerve supply on 14 ears of seven cadavers and find a heterogeneous distribution of two cranial branchial nerves and two somatic cervical nerves.
Abstract: Knowledge of the innervation of the outer ear is crucial for surgery in this region. The aim of this study was to describe the system of the auricular nerve supply. On 14 ears of seven cadavers the complete course of the nerve supply was exposed and categorized. A heterogeneous distribution of two cranial branchial nerves and two somatic cervical nerves was found. At the lateral as well as the medial surface the great auricular nerve prevails. No region with triple innervation was found. Clin. Anat. 15:35–37, 2002. © 2002 Wiley-Liss, Inc.

503 citations


"Optimization of Transcutaneous Vagu..." refers background in this paper

  • ...The earlobe is primarily innervated by the great auricular nerve that originates from the cervical nerve (C2); thus, CES does not stimulate the ABVN (21)....

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  • ...On the other hand, the cymba conchae was innervated by the ABVN in 100% of cases, which makes it a more attractive candidate and may have contributed to the fact that the cymba conchae performed better than the inner tragus in terms of stimulating the ABVN in the present study....

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  • ...To minimize these negative aspects, transcutaneous stimulation of the afferent auricular branch of the vagus nerve (ABVN) at the external ear has been considered as an alternative treatment option (15)....

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  • ...Three locations were selected for stimulation based on existing knowledge regarding the anatomical distribution of the ABVN (21–24), previous tVNS fMRI studies (16–19), and the stimulation locations for commercially available tVNS devices: the inner surface of the tragus, the inferoposterior wall of the external acoustic meatus (ear canal), and the cymba conchae....

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  • ...Although the cough reflex (Arnold’s reflex), which is induced by the mechanical stimulation of the ABVN, is consistently evoked by touching the inferoposterior wall of the ear canal, the ABVN location inside of the ear canal appears quite variable among subjects (21–23)....

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Journal ArticleDOI
TL;DR: VNS is now marketed throughout most of the world as a treatment for drug‐resistant epilepsy, but the therapeutic mechanism of action of VNS‐induced seizure suppression has not yet been established and elucidation of this mechanism is an important first step in the developed strategies to improve VNS efficacy.
Abstract: Summary: Purpose: Although vagus nerve stimulation (VNS) is now marketed throughout most of the world as a treatment for drug-resistant epilepsy, the therapeutic mechanism of action of VNS-induced seizure suppression has not yet been established. Elucidation of this mechanism is an important first step in the development of strategies to improve VNS efficacy. Because the locus coeruleus (LC) has been implicated in the antinociceptive effects of VNS, we chemically lesioned the LC in the present study to determine if it is a critical structure involved in the anticonvulsant mechanisms of VNS. Methods: Rats were chronically depleted of norepinephrine (NE) by a bilateral infusion of 6-hydroxydopamine (6-OHDA) into the LC. Two weeks later, they were tested with maximal electroshock (MES) to assess VNS-induced seizure suppression. In another experiment, the LC was acutely inactivated with lidocaine, and seizure suppression was tested in a similar fashion. Results: VNS significantly reduced seizure severities of control rats. However, in animals with chronic or acute LC lesions, VNS-induced seizure suppression was attenuated. Conclusions: Our data indicate that the LC is involved in the circuitry necessary for the anticonvulsant effects of VNS. Seizure suppression by VNS may therefore depend on the release of NE, a neuromodulator that has anticonvulsant effects. These data suggest that noradrenergic agonists might enhance VNS-induced seizure suppression.

499 citations


"Optimization of Transcutaneous Vagu..." refers background in this paper

  • ...The NTS projects to numerous areas in forebrain, limbic, and brainstem structures (17,19,20) including the LC, which is the major noradrenergic nucleus in the brain and plays a key role in the mechanisms of action underlying VNS (27,28,37,38)....

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Journal ArticleDOI
TL;DR: Findings in humans provide evidence in humans that the central projections of the ABVN are consistent with the "classical" central vagal projections and can be accessed non-invasively via the external ear.

434 citations


"Optimization of Transcutaneous Vagu..." refers background or methods in this paper

  • ...Only two of these studies reported activity in the NTS, which is the primary brain region receiving projections from the vagus nerve (17,19,20)....

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  • ...The NTS projects to numerous areas in forebrain, limbic, and brainstem structures (17,19,20) including the LC, which is the major noradrenergic nucleus in the brain and plays a key role in the mechanisms of action underlying VNS (27,28,37,38)....

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  • ...Only two studies have previously succeeded in demonstrating this type of activation (17,19), whereas another study reported only ipsilateral LC activation (18)....

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  • ...Four previous studies have investigated the effects of tVNS using fMRI, but several different areas of the ear were stimulated; namely, the inner wall of the tragus (16–18), the posterior side of the ear canal (17), and the cymba conchae (19)....

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  • ...First, the control location for the sham stimulation (earlobe) was chosen for the present study because a majority of previous tVNS studies (16,17,19) also used this location due to its proximity to other studied vagus-innervated locations and because it is known to be anatomically free of vagal innervation....

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