Cardiovascular autonomic effects of transcutaneous auricular nerve stimulation via the tragus in the rat involve spinal cervical sensory afferent pathways

Mahadi, Mohd Kaisan; Lall, Varinder K.; Deuchars, Susan A.; Deuchars, Jim

doi:10.1016/j.brs.2019.05.002

Cited by 34 publications

(37 citation statements)

References 46 publications

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“…In addition, LLTS stimulated antioxidant defense mechanisms by activating the Nrf2 pathway in the SP5 and SFO of HS diet animals. These results are consistent with a recent study which showed that the cardiovascular autonomic effect of tragus stimulation is mediated at least partly through spinal cervical sensory afferent pathways, including SP5 16 . Moreover, only sparse labeling of transganglionic tracer injected into the tragus of rats was found in NTS 16 .…”

Section: Discussionsupporting

confidence: 93%

Non-invasive vagus nerve stimulation attenuates proinflammatory cytokines and augments antioxidant levels in the brainstem and forebrain regions of Dahl salt sensitive rats

Subramanian

Edwards

Melton

et al. 2020

Sci Rep

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The anti-inflammatory effects of vagus nerve stimulation are well known. It has recently been shown that low-level, transcutaneous stimulation of vagus nerve at the tragus (LLTS) reduces cardiac inflammation in a rat model of heart failure with preserved ejection fraction (HFpEF). The mechanisms by which LLTS affect the central neural circuits within the brain regions that are important for the regulation of cardiac vagal tone are not clear. Female Dahl salt-sensitive rats were initially fed with either low salt (LS) or high salt (HS) diet for a period of 6 weeks, followed by sham or active stimulation (LLTS) for 30 min daily for 4 weeks. To study the central effects of LLTS, four brainstem (SP5, NAb, NTS, and RVLM) and two forebrain sites (PVN and SFO) were examined. HS diet significantly increased the gene expression of proinflammatory cytokines in the SP5 and SFO. LLTS reversed HS diet-induced changes at both these sites. Furthermore, LLTS augmented the levels of antioxidant Nrf2 in the SP5 and SFO. Taken together, these findings suggest that LLTS has central anti-inflammatory and antioxidant properties that could mediate the neuromodulation of cardiac vagal tone in the rat model of HFpEF.

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Section: Discussionsupporting

confidence: 93%

Non-invasive vagus nerve stimulation attenuates proinflammatory cytokines and augments antioxidant levels in the brainstem and forebrain regions of Dahl salt sensitive rats

Subramanian

Edwards

Melton

et al. 2020

Sci Rep

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“…Our previous neuro tracing study in rats showed dense termination of nerve afferents from the tragus into the ipsilateral dorsal region of the upper cervical spinal cord between C2 and C4 (Mahadi et al, 2019). Further neurophysiology recordings from the central sympathetic trunk showed acute reductions in sympathetic activity after tragus stimulation; equivalent as per reported in healthy humans (Clancy et al, 2014;Mahadi et al, 2019). Interestingly, the inhibitory effect persisted despite cervical vagal sectioning ipsilateral to the stimulation point.…”

Section: Perspectives and Future Studies How Does Auricular Stimulatisupporting

confidence: 66%

“…The cardioprotective effects of VNS involve activation of the CAP which may reprogram and rebalance the production of inflammatory cytokines (Figure 2). However, recent findings suggest that other neural pathways such as cervical spinal activation may be involved in auricular tVNS (Mahadi et al, 2019). It remains unknown how tVNS may activate the CAP in cardiac macrophages similar to that shown in invasive VNS.…”

Section: Resultsmentioning

confidence: 97%

“…It is important to note that although other nerves innervate the auricle, e.g., the great auricular nerve and the auriculotemporal nerve, they are often underappreciated and findings are based on one research study (Peuker and Filler, 2002;Burger and Verkuil, 2018). Our previous neuro tracing study in rats showed dense termination of nerve afferents from the tragus into the ipsilateral dorsal region of the upper cervical spinal cord between C2 and C4 (Mahadi et al, 2019). Further neurophysiology recordings from the central sympathetic trunk showed acute reductions in sympathetic activity after tragus stimulation; equivalent as per reported in healthy humans (Clancy et al, 2014;Mahadi et al, 2019).…”

Section: Perspectives and Future Studies How Does Auricular Stimulatimentioning

confidence: 99%

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Mediation of Cardiac Macrophage Activity via Auricular Vagal Nerve Stimulation Ameliorates Cardiac Ischemia/Reperfusion Injury

et al. 2020

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Background: Myocardial infarction (MI) reperfusion therapy causes paradoxical cardiac complications. Following restoration of blood flow to infarcted regions, a multitude of inflammatory cells are recruited to the site of injury for tissue repair. Continual progression of cardiac inflammatory responses does, however, lead to adverse cardiac remodeling, inevitably causing heart failure. Main Body: Increasing evidence of the cardioprotective effects of both invasive and non-invasive vagal nerve stimulation (VNS) suggests that these may be feasible methods to treat myocardial ischemia/reperfusion injury via anti-inflammatory regulation. The mechanisms through which auricular VNS controls inflammation are yet to be explored. In this review, we discuss the potential of autonomic nervous system modulation, particularly via the parasympathetic branch, in ameliorating MI. Novel insights are provided about the activation of the cholinergic anti-inflammatory pathway on cardiac macrophages. Acetylcholine binding to the α7 nicotinic acetylcholine receptor (α7nAChR) expressed on macrophages polarizes the pro-inflammatory into anti-inflammatory subtypes. Activation of the α7nAChR stimulates the signal transducer and activator of transcription 3 (STAT3) signaling pathway. This inhibits the secretion of pro-inflammatory cytokines, limiting ischemic injury in the myocardium and initiating efficient reparative mechanisms. We highlight recent developments in the controversial auricular vagal neuro-circuitry and how they may relate to activation of the cholinergic anti-inflammatory pathway. Conclusion: Emerging published data suggest that auricular VNS is an inexpensive healthcare modality, mediating the dynamic balance between pro-and anti-inflammatory responses in cardiac macrophages and ameliorating cardiac ischemia/reperfusion injury.

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“…More surprisingly, our response cluster possibly extends to the dorsal column nuclei, namely gracilis and cuneatus, known to relay touch and proprioceptive afference from the lower and upper body, respectively [46]. A possible explanation for their involvement can be found in a recent study by Mahadi and coauthors [51], who investigated the central projections from nerves innervating the tragus in rats. Their findings showed dense labeling in the cervical spinal cord, as well as sensory nuclei in the medulla, thus suggesting the existence of a spinal cervical sensory pathway for tragus electrical stimulation effects.…”

Section: Discussionmentioning

confidence: 77%

Stimulus frequency modulates brainstem response to respiratory-gated transcutaneous auricular vagus nerve stimulation

et al. 2020

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a b s t r a c tBackground: The therapeutic potential of transcutaneous auricular VNS (taVNS) is currently being explored for numerous clinical applications. However, optimized response for different clinical indications may depend on specific neuromodulation parameters, and systematic assessments of their influence are still needed to optimize this promising approach. Hypothesis: We proposed that stimulation frequency would have a significant effect on nucleus tractus solitarii (NTS) functional MRI (fMRI) response to respiratory-gated taVNS (RAVANS). Methods: Brainstem fMRI response to auricular RAVANS (cymba conchae) was assessed for four different stimulation frequencies (2, 10, 25, 100 Hz). Sham (no current) stimulation was used to control for respiration effects on fMRI signal. Results: Our findings demonstrated that RAVANS delivered at 100 Hz evoked the strongest brainstem response, localized to a cluster in the left (ipsilateral) medulla and consistent with purported NTS. A colocalized, although weaker, response was found for 2 Hz RAVANS. Furthermore, RAVANS delivered at 100 Hz also evoked stronger fMRI responses for important monoamine neurotransmitter source nuclei (LC, noradrenergic; MR, DR, serotonergic) and pain/homeostatic regulation nuclei (i.e. PAG). Conclusion: Our fMRI results support previous localization of taVNS afference to pontomedullary aspect of NTS in the human brainstem, and demonstrate the significant influence of the stimulation frequency on brainstem fMRI response.

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Cardiovascular autonomic effects of transcutaneous auricular nerve stimulation via the tragus in the rat involve spinal cervical sensory afferent pathways

Abstract: This is a repository copy of Cardiovascular autonomic effects of transcutaneous auricular nerve stimulation via the tragus in the rat involve spinal cervical sensory afferent pathways..

Cited by 34 publications

References 46 publications

Non-invasive vagus nerve stimulation attenuates proinflammatory cytokines and augments antioxidant levels in the brainstem and forebrain regions of Dahl salt sensitive rats

Non-invasive vagus nerve stimulation attenuates proinflammatory cytokines and augments antioxidant levels in the brainstem and forebrain regions of Dahl salt sensitive rats

Mediation of Cardiac Macrophage Activity via Auricular Vagal Nerve Stimulation Ameliorates Cardiac Ischemia/Reperfusion Injury

Stimulus frequency modulates brainstem response to respiratory-gated transcutaneous auricular vagus nerve stimulation

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