Original ArticleThe effect of transcutaneous vagus nerve stimulation on pain perception – An experimental study
Introduction
Recent work suggests that the vagus nerve, traditionally considered a purely parasympathetic efferent nerve, provides an exceeding important route for information into the central nervous system [1]. In the past few years, vagus nerve stimulation (VNS) has been developed as a method to physically alter relevant brain functions, thus offering a clinically useful non drug-based anticonvulsive and antidepressant therapy option [1], [2].
The known anatomic projections of the vagus nerve and its association with many different brain functions involved in the perception of pain suggest that VNS might also have applications in the therapy of different pain syndromes. Several experimental animal studies in mammals have demonstrated an inhibitory effect of VNS on the electric response of spinal nociceptive neurons as well as on nociceptive behavior [3], [4], [5], [6], [7]. The neurophysiological data from these animal experiments are supported by some observational studies in humans, suggesting a pain-modulating effect of vagus nerve stimulation under conventional VNS. With regard to headache syndromes, several case reports [8], [9], [10] and one observational report on 4 therapy-refractory migraine and 2 cluster headache patients exist [11] underlining a reduction of headache frequency or intensity following VNS in patients with seizures, who concurrently suffered from migraine.
Invasive VNS is an approved treatment for drug-resistant epilepsy [2]. Besides recognized clinical efficacy there are some disadvantages including the irreversible nature of the electrode implant in the majority of cases, electrode fractures, deep wound infections, transient vocal cord palsy, cardiac arrhythmia under test stimulation, electrode malfunction, and posttraumatic dysfunction of the stimulator [12]. Frequent side effects of chronic, invasive VNS such as hoarseness, cough, dyspnea, and pain are mainly due to bidirectional stimulation of efferent and afferent fibers within the mixed cervical branch of the vagus nerve. Invasiveness and adverse events of VNS have hampered the conduction of clinical trials in other indications than epilepsies. The recently introduced technique of transcutaneous vagus nerve stimulation (t-VNS®) [13] combines selective, non-invasive and reversible access to vagus nerve afferents with a low risk profile. t-VNS targets the cutaneous receptive field of the auricular branch of the vagus nerve at the outer ear (inner side of the tragus) [14] and has been shown to activate cerebral vagal patterns in f-MRI studies [15], [16]. Several lines of evidence from anatomical and clinical studies reveal the topographic anatomy and the functional impact of the auricular branch of the vagus nerve on the autonomic nervous system [17]. Both invasive and transcutaneous VNS excite thick-myelinated fibers of vagus nerve branches that project to the main therapeutic target the nucleus of the solitary tract in the brainstem. Preclinical data emphasize equivalent anticonvulsive effects of both methods [18]. Based upon the common mode of action of invasive and transcutaneous VNS and first clinical data, the t-VNS® device received CE approval for the intended use in drug-resistant epilepsy and depression.
Our study aimed at investigating pain perception during a t-VNS approach in a sample of 48 healthy subjects using a randomized, controlled, double-blinded cross-over design. For assessing different submodalities of peripheral and central nociception, we used the quantitative sensory testing procedure developed by the German Research Network on Neuropathic Pain including a tonic heat pain paradigm to obtain a full sensory profile of each single subject [19]. We also investigated whether t-VNS had an effect on the parameters of the autonomic nervous system (skin conductance levels, heart rates and respiration activity).
Section snippets
Study
The study was approved by the local ethics committee (University of Regensburg, Germany, Proposal Nr. 09/119). Informed consent was obtained from all subjects.
Subjects
Forty-eight healthy subjects were finally enrolled in the study. All subjects were undergraduate students from the local university. They underwent a neurological examination and were interviewed by a psychiatrist, who additionally administered the SCID-1 Screening instrument [20], [21]. Exclusion criteria were the history of a migraine,
Subjects
Two subjects were not compliant to the protocol and were excluded from further analyses. They were replaced by two new subjects recruited at the end of the study. The final sample consisted of 48 healthy students (24 female, 24 male) with a mean age of 23.3 ± 2.1 years (range 20–28 years). All of these subjects completed the study.
The mean BDI score of the final sample was 2.1 ± 2.1. The mean SOMS-2a score was 1.2 ± 1.6. The mean STAI (state) score was 31.2 ± 6.4.
Pain measurements
Only one subject revealed VDT
Summary of findings
Based on a randomized, double-blinded and controlled cross-over design, our study focused on the effect of t-VNS on human pain processing by measuring a set of relevant submodalities of the somatosensory system using a comprehensive quantifiable testing protocol (including a tonic heat pain paradigm) before and during active t-VNS or sham t-VNS applications in a sample of 48 healthy volunteers.
We found a bilateral inhibition of pain sensitivity during 5 min of tonic heat pain following 1 h of a
Conclusion
Taken together, our results demonstrate that t-VNS decisively influences pain processings in healthy humans. To the best of our knowledge, this study is the first demonstrating an inhibitory effect of a continuous transcutaneous vagus nerve stimulation on different pain modalities in healthy subjects. Based on a controlled experimental study design, we could contribute to the most recent work identifying an inhibitory effect of t-VNS, specific for mechanical and tonic heat pain stimuli, whereas
Authors approval
All authors have personally reviewed and given final approval of the version submitted, and neither the manuscript, nor its data have been previously published or are currently under consideration of publication.
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Cited by (0)
The study was sponsored by the device manufacturer Fa. Cerbomed (Erlangen, Germany). Apart from that, no financial or personal relationship and affiliations relevant to the subject matter of the manuscript have occurred within the last two years or are expected in future. No otherwise grants or funding have been paid.