The vagus nerve (cranial nerve X) is a mixed nerve composed of 20% efferent
fibers (sending signals from the brain to the body) and 80% afferent
(sensory) fibers (carrying information from the body to the brain). Vagus nerve stimulation
(VNS) refers to any technique that stimulates the nerve, such as manual or electrical stimulation. Clinical trials led to approval by the U.S. Food and Drug Administration (FDA) of an implanted VNS device indicated for the treatment of refractory epilepsy in 1997. The same device was later given an FDA-approved indication for the treatment of chronic treatment-resistant depression (TRD) in 2005. I previously described VNS and its use for depression and other neuropsychiatric disorders (Howland, 2006a, 2006b
). This month, I will review new developments with VNS therapy.
Left Cervical VNS
For epilepsy and depression, the programmable device is surgically implanted in the left upper chest and connected by a lead wire to the left cervical vagus nerve (located in the mid-neck region). Berry et al. (2013) recently published a meta-analysis of patient-level data from six multicenter studies of left cervical VNS for chronic TRD. They compared response and remission rates (based on the Montgomery-Asberg Depression Rating Scale [MADRS] and the Clinical Global Impressions Improvement [CGI-I] subscale) during approximately 2 years of follow-up treatment for 1,035 patients receiving VNS plus treatment as usual (VNS+TAU) and 425 patients receiving only TAU. The MADRS response rates for VNS+TAU at 12, 24, 48, and 96 weeks were 12%, 18%, 28%, and 32%, respectively, versus 4%, 7%, 12%, and 14%, respectively, for TAU. The MADRS remission rates were 3%, 5%, 10%, and 14%, respectively, for VNS+TAU versus 1%, 1%, 2%, and 4%, respectively, for TAU. Similar findings were seen using CGI data. When outcome data were analyzed using odds ratios, VNS+TAU was associated with a significantly greater likelihood of response and remission compared with TAU. For patients who had responded to VNS+TAU at 24 weeks, sustained response was more likely at 48 and 96 weeks.
A nonrandomized registry study (Olin, Jayewardene, Bunker, & Moreno, 2012) compared VNS+TAU (335 patients) versus TAU (301 patients). The registry found that VNS-treated patients have lower rates of all-cause mortality, completed suicide, suicidal thoughts, and suicidal attempts compared to TAU patients, although not all of the findings were statistically significant. In a retrospective analysis of Medicare administrative claims data, Feldman, Dunner, Muller, and Stone (2012) compared the experience of four groups of Medicare beneficiaries: (a) those receiving left cervical VNS; (b) those defined as having TRD; (c) those defined as having non-TRD; and (d) those defined as general Medicare beneficiaries. Patients receiving VNS had lower annual mortality rates compared to the three other groups. The medical costs per patient-year were found to be similar for the VNS and non-TRD groups, both of which were substantially lower than for the TRD group.
Right Cervical VNS
Left cervical VNS was investigated and approved for the treatment of epilepsy and TRD, and right cervical VNS was avoided to minimize potential adverse cardiac effects (e.g., bradycardia). Animal and human studies, however, suggest that right cervical VNS is effective for treating heart failure and arrhythmias (De Ferrari & Schwartz, 2011). Right cervical VNS reduces seizure activity in animal models, and there is some evidence that this is true in humans, but its antidepressant effect is unknown. A VNS device system (CardioFit® System) was developed for the treatment of heart failure. This programmable device is implanted in the right chest wall and connected to the right cervical vagus nerve using a cuff designed to preferentially activate vagal efferent fibers (intended to affect cardiac function). The stimulator senses heart rate and shuts off at a predetermined threshold of bradycardia. Preclinical studies and one Phase II human study suggest that chronic right cervical VNS is safe and effective for heart failure (De Ferrari et al., 2011).
A similar VNS system (FitNeS® System) was designed using a cuff electrode preferentially activating vagal afferent fibers to minimize typical VNS side effects associated with efferent fiber stimulation (i.e., voice alteration, cough, dyspnea, dysphagia, and neck pain or paresthesias). Left cervical VNS using this device has been described in five patients with epilepsy, showing some benefit and no typical VNS side effects (Ben-Menachem, Rydenhag, & Silander, 2013), but it has not been studied for chronic TRD.
The outer ear is supplied by three sensory nerves, including the auricular branch of the vagus nerve (ABVN) (Ellrich, 2011). Holding a fingertip at the entrance of the ear canal and tracing the tip backward, upward, and forward naturally traces a reverse “C” along this groove. Sensory fibers from the ABVN supply the skin of this “reverse C” groove. The cymba conchae is the furrow situated at the top of this reverse C and it is supplied exclusively by the ABVN. Applying an electrical stimulus (intensity above the sensory detection threshold, but below the pain threshold) to this region of the ear, especially the left cymba conchae, results in a brain activation pattern not unlike that seen with left cervical VNS (Kraus et al., 2013). A transcutaneous method of VNS (t-VNS) could therefore be used to target the ABVN cutaneous receptive field.
The use of t-VNS for treating epilepsy was first proposed by Ventureyra (2000). A t-VNS device (NEMOS®) received European clearance for the treatment of epilepsy and depression in 2010 and for the treatment of pain in 2012. These approvals were based primarily on preclinical studies of t-VNS, as well as extrapolating the findings from preclinical and human studies of left cervical VNS.
Transcutaneous electrical nerve stimulator (TENS) devices can also be used to administer t-VNS by situating contact electrodes on the ear in the region of the ABVN as described above. Patients can self-administer t-VNS, which can be applied unilaterally or bilaterally (depending on the device system used). There is no established clinical paradigm for how t-VNS should be administered (e.g., stimulation parameters, duration and frequency of each stimulation session, length of treatment). The NEMOS manufacturer suggests that each session last at least 1 hour and should be used three to four times per day, but the basis for this recommendation is unclear. Published clinical data (mostly pilot studies) on the use of t-VNS for epilepsy, depression, pain, and other clinical indications suggest that it is safe and well tolerated (Busch et al., 2013; Lehtimäki et al., 2013; Stefan et al., 2012).
Hein et al. (2013) conducted a randomized sham-controlled pilot study of t-VNS in 37 patients with major depression (not TRD). The t-VNS was administered bilaterally using a TENS microstimulator unit (NET-2000 and NET-1000 devices, manufactured by Auri-Stim Medical Inc., Denver, CO). The stimulation was used for 15 minutes once or twice per day, 5 days per week, for 2 weeks. Active stimulation was set just below the threshold of perception; sham stimulation involved no current. Active-stimulation was associated with a significantly greater improvement on a self-report measure of depression (Beck Depression Inventory) compared to sham-stimulation after 2 weeks, but there was no change within or difference between groups on a clinicianrated measure of depression (Hamilton Rating Scale for Depression). The treatment was well tolerated. Another study of t-VNS for non-chronic depression is currently being conducted (discussed in Rong et al., 2012).
Vagus Nerve and Neuro-Endocrine-Immune Axis
The vagus nerve is a major component of the sympathetic-parasympathetic autonomic nervous system, has an important role in the regulation of metabolic homeostasis, and plays a key role in the regulation of the neuro-endocrine-immune axis (Bonaz, Picq, Sinniger, Mayol, & Clarençon, 2013; Pavlov & Tracey, 2012). Stimulation of immune cells by foreign pathogens induces the secretion of proinflammatory cytokines that communicate with the brain through neural and humoral pathways. The vagus nerve mediates an anti-inflammatory effect through its afferent pathways (regulation of the hypothalamic-pituitary-adrenal axis and adrenal gland corticosteroid release). Vagus nerve efferents mediate anti-inflammatory processes via direct effects on immune cells and through the splenic sympathetic nerve. This pathway is referred to as the cholinergic anti-inflammatory pathway (CAP). Activation of vagal afferents by cytokines and other inflammatory mediators in peripheral tissues results in an inflammatory reflex in which vagal efferents inhibit inflammation by suppressing cytokine production via the CAP.
Experimental animal studies have demonstrated that invasive VNS significantly alters proinflammatory cytokines and other measures of inflammation (Bonaz et al., 2013). Right and left VNS also has favorable effects on cerebral ischemia in animals, which does not appear to be related to alterations in cerebral blood flow. t-VNS reduced proinflammatory biomarkers and improved survival in a murine (mouse) sepsis model (Huston et al., 2007). Some clinical studies of inflammatory markers in VNS-treated epilepsy patients demonstrated alterations associated with VNS (e.g., Majoie et al., 2011). Corcoran, Connor, O’Keane, and Garland (2005) measured various peripheral cytokines before and 3 months after left cervical VNS implantation in 10 patients with TRD. They found increases in certain proinflammatory and anti-inflammatory peripheral cytokines.
Antidepressant therapies can suppress or attenuate proinflammatory processes (Leonard, 2014), although the presence of inflammatory biomarkers is associated with a suboptimal antidepressant response (Raison et al., 2013). Novel pharmacological agents targeting inflammatory processes are being investigated as possible antidepressant therapies (Raison et al., 2013). Neuro-endocrine-immune axis regulation might be a potential antidepressant mechanism of action for VNS. Using VNS as an antidepressant might have primary, secondary, or tertiary prevention benefits for cardiocerebrovascular disease, metabolic syndrome, and other inflammatory conditions associated with depression (Pavlov & Tracey, 2012).
Left cervical VNS is an approved therapy for epilepsy and chronic TRD. The tolerability and safety of implanted VNS systems has been well established based on worldwide experience with depression and epilepsy patients, including children and adolescents with epilepsy. Animal and human studies suggest that right cervical VNS is effective for treating heart failure and arrhythmias. Whether right, left, and bilateral cervical VNS have comparable effects in the treatment of epilepsy or depression in humans is unknown. In patients with depression, it is also unknown whether the potential benefits of VNS on cardiovascular, cerebrovascular, and metabolic risk factors would differ for right, left, or bilateral VNS. t-VNS is a potentially viable nonsurgical option that could be managed by nurses. Although its antidepressant efficacy has not been established and its effect on inflammatory biomarkers has not been extensively investigated in humans, t-VNS deserves further study.
- Ben-Menachem, E., Rydenhag, B. & Silander, H. (2013). Preliminary experience with a new system for vagus nerve stimulation for the treatment of refractory focal onset seizures. Epilepsy Behavior, 29, 416–419. doi:10.1016/j.yebeh.2013.08.014 [CrossRef]
- Berry, S.M., Broglio, K., Bunker, M., Jayewardene, A., Olin, B. & Rush, A.J. (2013). A patient-level meta-analysis of studies evaluating vagus nerve stimulation therapy for treatment-resistant depression. Medical Devices Evidence Research, 6, 17–35. doi:10.2147/MDER.S41017 [CrossRef]
- Bonaz, B., Picq, C., Sinniger, V., Mayol, J.F. & Clarençon, D. (2013). Vagus nerve stimulation: From epilepsy to the cholinergic anti-inflammatory pathway. Neurogastroenterology Motility, 25, 208–221. doi:10.1111/nmo.12076 [CrossRef]
- Busch, V., Zeman, F., Heckel, A., Menne, F., Ellrich, J. & Eichhammer, P. (2013). The effect of transcutaneous vagus nerve stimulation on pain perception—An experimental study. Brain Stimulation, 6, 202–209. doi:10.1016/j.brs.2012.04.006 [CrossRef]
- Corcoran, C., Connor, T.J., O’Keane, V. & Garland, M.R. (2005). The effects of vagus nerve stimulation on pro- and anti-inflammatory cytokines in humans: A preliminary report. Neuroimmunomodulation, 12, 307–309. doi:10.1159/000087109 [CrossRef]
- De Ferrari, G.M., Crijns, H.J.G.M., Borggrefe, M., Smid, J., Zabel, M., Gavazzi, A. & Schwartz, P.J. (2011). Chronic vagus nerve stimulation: A new and promising therapeutic approach for chronic heart failure. European Heart Journal, 32, 847–855. doi:10.1093/eurheartj/ehq391 [CrossRef]
- De Ferrari, G.M. & Schwartz, P.J. (2011). Vagus nerve stimulation: From pre-clinical to clinical application: Challenges and future directions. Heart Failure Reviews, 16, 195–203. doi:10.1007/s10741-010-9216-0 [CrossRef]
- Ellrich, J. (2011). Transcutaneous vagus nerve stimulation. European Neurological Review, 6, 254–256.
- Feldman, R.L., Dunner, D.L., Muller, J.S. & Stone, D.A. (2012). Medicare patient experience with vagus nerve stimulation for treatment-resistant depression. Journal of Medical Economics, 16, 62–74. doi:10.3111/13696998.2012.724745 [CrossRef]
- Hein, E., Nowak, M., Kiess, O., Biermann, T., Bayerlein, K., Kornhuber, J. & Kraus, T. (2013). Auricular transcutaneous electrical nerve stimulation in depressed patients: A randomized controlled pilot study. Journal of Neural Transmission, 120, 821–827. doi:10.1007/s00702-012-0908-6 [CrossRef]
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- Huston, J.M., Gallowitsche-Puerta, M., Ochani, M., Ochani, K., Yuan, R., Rosas-Ballina, M. & Tracey, K.J. (2007). Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis. Critical Care Medicine, 35, 2762–2768. doi:10.1097/01.CCM.0000288102.15975.BA [CrossRef]
- Kraus, T., Kiess, O., Hösl, K., Terekhin, P., Kornhuber, J. & Forster, C. (2013). CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal—A pilot study. Brain Stimulation, 6, 798–804. doi:10.1016/j.brs.2013.01.011 [CrossRef]
- Lehtimäki, J., Hyvärinen, P., Ylikoski, M., Bergholm, M., Mäkelä, J.P., Aarnisalo, A. & Ylikoski, J. (2013). Transcutaneous vagus nerve stimulation in tinnitus: A pilot study. Acta Otolaryngologica, 133, 378–382. doi:10.3109/00016489.2012.750736 [CrossRef]
- Leonard, B.E. (2014). Impact of inflammation on neurotransmitter changes in major depression: An insight into the action of anti-depressants. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 48, 261–267. doi:10.1016/j.pnpbp.2013.10.018 [CrossRef]
- Majoie, H.J., Rijkers, K., Berfelo, M.W., Hulsman, J.A., Myint, A., Schwarz, M. & Vles, J.S. (2011). Vagus nerve stimulation in refractory epilepsy: Effects on pro- and anti-inflammatory cytokines in peripheral blood. Neuroimmunomodulation, 18, 52–56. doi:10.1159/000315530 [CrossRef]
- Olin, B., Jayewardene, A.K., Bunker, M. & Moreno, F. (2012). Mortality and suicide risk in treatment-resistant depression: An observational study of the long-term impact of intervention. PLoS One, 7, e48002. doi:10.1371/journal.pone.0048002 [CrossRef]
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- Raison, C.L., Rutherford, R.E., Woolwine, B.J., Shuo, C., Schettler, P., Drake, D.F. & Miller, A.H. (2013). A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers. Journal of the American Medical Association Psychiatry, 70, 31–41. doi:10.1001/2013.jamapsychiatry.4 [CrossRef]
- Rong, P.J., Fang, J.L., Wang, L.P., Meng, H., Liu, J., Ma, Y.G. & Kong, J. (2012). Transcutaneous vagus nerve stimulation for the treatment of depression: A study protocol for a double blinded randomized clinical trial. BMC Complementary Alternative Medicine, 12, 255. doi:10.1186/1472-6882-12-255 [CrossRef]
- Stefan, H., Kreiselmeyer, G., Kerling, F., Kurzbuch, K., Rauch, C., Heers, M. & Hopfengärtner, R. (2012). Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: A proof of concept trial. Epilepsia, 53(7), e115–e118. doi:10.1111/j.1528-1167.2012.03492.x [CrossRef]
- Ventureyra, E.C. (2000). Transcutaneous vagus nerve stimulation for partial onset seizure therapy. A new concept. Child’s Nervous System, 16, 101–102. doi:10.1007/s003810050021 [CrossRef]