, Volume 14, Issue 3, pp 716–727 | Cite as

Vagal Nerve Stimulation for Treatment-Resistant Depression



Major depressive disorder (MDD) is prevalent. Although standards antidepressants are more effective than placebo, up to 35% of patients do not respond to 4 or more conventional treatments and are considered to have treatment-resistant depression (TRD). Considerable effort has been devoted to trying to find effective treatments for TRD. This review focuses on vagus nerve stimulation (VNS), approved for TRD in 2005 by the Food and Drugs Administration. Stimulation is carried by bipolar electrodes on the left cervical vagus nerve, which are attached to an implanted stimulator generator. The vagus bundle contains about 80% of afferent fibers terminating in the medulla, from which there are projections to many areas of brain, including the limbic forebrain. Various types of brain imaging studies reveal widespread functional effects in brain after either acute or chronic VNS. Although more randomized control trials of VNS need to be carried out before a definitive conclusion can be reached about its efficacy, the results of open studies, carried out over period of 1 to 2 years, show much more efficacy when compared with results from treatment as usual studies. There is an increase in clinical response to VNS between 3 and 12 months, which is quite different from that seen with standard antidepressant treatment of MDD. Preclinically, VNS affects many of the same brain areas, neurotransmitters (serotonin, norepinephrine) and signal transduction mechanisms (brain-derived neurotrophic factor–tropomyosin receptor kinase B) 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.


TRD VNS BDNF-TrkB Monoamines 



We thank William R. Buras, formerly an employee of Cyberonics, Inc., the manufacturer of the VNS device, who is currently at Tietronix, Inc., Houston, TX, for reviewing and giving insightful suggestions on an earlier version of this manuscript. Dr. Frazer has not had involvements with Cyberonics, Inc. for over 5 years. He had previously been on one of their advisory boards and has received a grant from Cyberonics for some of his preclinical studies involving VNS. Dr. Carreno has no financial conflicts to disclose.

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  1. 1.
    Kessler, R.C., S. Avenevoli, K.A. McLaughlin, J.G. Green, M.D. Lakoma, et al., Lifetime co-morbidity of DSM-IV disorders in the US National Comorbidity Survey Replication Adolescent Supplement (NCS-A). Psychol Med, 2012. 42(9): p. 1997-2010.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Leucht, S., S. Hierl, W. Kissling, M. Dold, and J.M. Davis, Putting the efficacy of psychiatric and general medicine medication into perspective: review of meta-analyses. Br J Psychiatry, 2012. 200(2): p. 97-106.PubMedCrossRefGoogle Scholar
  3. 3.
    Rush, A.J., Limitations in efficacy of antidepressant monotherapy. J Clin Psychiatry, 2007. 68 Suppl 10: p. 8-10.PubMedGoogle Scholar
  4. 4.
    Kennedy, N. and K. Foy, The impact of residual symptoms on outcome of major depression. Curr Psychiatry Rep, 2005. 7(6): p. 441-446.PubMedCrossRefGoogle Scholar
  5. 5.
    Kennedy, N. and E.S. Paykel, Residual symptoms at remission from depression: impact on long-term outcome. J Affect Disord, 2004. 80(2-3): p. 135-144.PubMedCrossRefGoogle Scholar
  6. 6.
    Pintor, L., C. Gasto, V. Navarro, X. Torres, and L. Fananas, Relapse of major depression after complete and partial remission during a 2-year follow-up. J Affect Disord, 2003. 73(3): p. 237-244.PubMedCrossRefGoogle Scholar
  7. 7.
    Rush, A.J., H.C. Kraemer, H.A. Sackeim, M. Fava, M.H. Trivedi, et al., Report by the ACNP Task Force on response and remission in major depressive disorder. Neuropsychopharmacology, 2006. 31(9): p. 1841-1853.PubMedCrossRefGoogle Scholar
  8. 8.
    Fekadu, A., S.C. Wooderson, K. Markopoulo, C. Donaldson, A. Papadopoulos, et al., What happens to patients with treatment-resistant depression? A systematic review of medium to long term outcome studies. J Affect Disord, 2009. 116(1-2): p. 4-11.PubMedCrossRefGoogle Scholar
  9. 9.
    Mrazek, D.A., J.C. Hornberger, C.A. Altar, and I. Degtiar, A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013. Psychiatr Serv, 2014. 65(8): p. 977-987.PubMedCrossRefGoogle Scholar
  10. 10.
    Prudic, J., M. Olfson, S.C. Marcus, R.B. Fuller, and H.A. Sackeim, Effectiveness of electroconvulsive therapy in community settings. Biol Psychiatry, 2004. 55(3): p. 301-312.PubMedCrossRefGoogle Scholar
  11. 11.
    Stegenga, B.T., M.H. Kamphuis, M. King, I. Nazareth, and M.I. Geerlings, The natural course and outcome of major depressive disorder in primary care: the PREDICT-NL study. Soc Psychiatry Psychiatr Epidemiol, 2012. 47(1): p. 87-95.PubMedCrossRefGoogle Scholar
  12. 12.
    Bewernick, B. and T.E. Schlaepfer, Update on Neuromodulation for Treatment-Resistant Depression. F1000Res, 2015. 4.Google Scholar
  13. 13.
    Foley, J.O. and F.S. DuBois, Quantitative studies of the vagus nerve in the cat. I. The ratio of sensory to motor fibers. J. Comp. Neurol., 1937. 67: p. 49-67.Google Scholar
  14. 14.
    Bailey, P. and F. Bremer, A sensory cortical representation of the vagus nerve. J Neurophysiol, 1938. 1:p. 405-412.Google Scholar
  15. 15.
    Berthoud, H.R. and W.L. Neuhuber, Functional and chemical anatomy of the afferent vagal system. Auton Neurosci, 2000. 85(1-3): p. 1-17.PubMedCrossRefGoogle Scholar
  16. 16.
    George, M.S. and G. Aston-Jones, Noninvasive techniques for probing neurocircuitry and treating illness: vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). Neuropsychopharmacology, 2010. 35(1): p. 301-316.PubMedCrossRefGoogle Scholar
  17. 17.
    Yuan, H. and S.D. Silberstein, Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part I. Headache, 2016. 56(1): p. 71-78.PubMedCrossRefGoogle Scholar
  18. 18.
    Randall, W.C. and J.L. Ardell, Selective parasympathectomy of automatic and conductile tissues of the canine heart. Am J Physiol, 1985. 248(1 Pt 2): p. H61-H68.PubMedGoogle Scholar
  19. 19.
    Woodbury, D.M. and J.W. Woodbury, Effects of vagal stimulation on experimentally induced seizures in rats. Epilepsia, 1990. 31 Suppl 2: p. S7-S19.PubMedCrossRefGoogle Scholar
  20. 20.
    Agnew, W.F. and D.B. McCreery, Considerations for safety with chronically implanted nerve electrodes. Epilepsia, 1990. 31 Suppl 2: p. S27-S32.PubMedCrossRefGoogle Scholar
  21. 21.
    Penry, J.K. and J.C. Dean, Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. Epilepsia, 1990. 31 Suppl 2: p. S40-S43.PubMedCrossRefGoogle Scholar
  22. 22.
    Elger, G., C. Hoppe, P. Falkai, A.J. Rush, and C.E. Elger, Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res, 2000. 42(2-3): p. 203-210.PubMedCrossRefGoogle Scholar
  23. 23.
    Aaronson, S.T., L.L. Carpenter, C.R. Conway, F.W. Reimherr, S.H. Lisanby, et al., Vagus nerve stimulation therapy randomized to different amounts of electrical charge for treatment-resistant depression: acute and chronic effects. Brain Stimul, 2013. 6(4): p. 631-640.PubMedCrossRefGoogle Scholar
  24. 24.
    Muller, H.H., J. Kornhuber, J.M. Maler, and W. Sperling, The effects of stimulation parameters on clinical outcomes in patients with vagus nerve stimulation implants with major depression. J ECT, 2013. 29(3): p. e40-e42.PubMedCrossRefGoogle Scholar
  25. 25.
    Lomarev, M., S. Denslow, Z. Nahas, J.H. Chae, M.S. George, et al., Vagus nerve stimulation (VNS) synchronized BOLD fMRI suggests that VNS in depressed adults has frequency/dose dependent effects. J Psychiatr Res, 2002. 36(4): p. 219-227.PubMedCrossRefGoogle Scholar
  26. 26.
    Berry, S.M., K. Broglio, M. Bunker, A. Jayewardene, B. Olin, et al., A patient-level meta-analysis of studies evaluating vagus nerve stimulation therapy for treatment-resistant depression. Med Devices (Auckl), 2013. 6: p. 17-35.Google Scholar
  27. 27.
    Blumberger, D.M., J.H. Hsu, and Z.J. Daskalakis, A Review of Brain Stimulation Treatments for Late-Life Depression. Curr Treat Options Psychiatry, 2015. 2(4): p. 413-421.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Cimpianu, C.L., W. Strube, P. Falkai, U. Palm, and A. Hasan, Vagus nerve stimulation in psychiatry: a systematic review of the available evidence. J Neural Transm (Vienna), 2017; 124:145-158.CrossRefGoogle Scholar
  29. 29.
    Groves, D.A. and V.J. Brown, Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neurosci Biobehav Rev, 2005. 29(3): p. 493-500.PubMedCrossRefGoogle Scholar
  30. 30.
    Martin, J.L. and E. Martin-Sanchez, Systematic review and meta-analysis of vagus nerve stimulation in the treatment of depression: variable results based on study designs. Eur Psychiatry, 2012. 27(3): p. 147-155.PubMedCrossRefGoogle Scholar
  31. 31.
    Nemeroff, C.B., H.S. Mayberg, S.E. Krahl, J. McNamara, A. Frazer, et al., VNS therapy in treatmentresistant depression: clinical evidence and putative neurobiological mechanisms. Neuropsychopharmacology, 2006. 31(7): p. 1345-1355.PubMedCrossRefGoogle Scholar
  32. 32.
    Rush, A.J. and S.E. Siefert, Clinical issues in considering vagus nerve stimulation for treatment-resistant depression. Exp Neurol, 2009. 219(1): p. 36-43.PubMedCrossRefGoogle Scholar
  33. 33.
    Shah, A., F.R. Carreno, and A. Frazer, Therapeutic modalities for treatment resistant depression: focus on vagal nerve stimulation and ketamine. Clin Psychopharmacol Neurosci, 2014. 12(2): p. 83-93.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Beekwilder, J.P. and T. Beems, Overview of the clinical applications of vagus nerve stimulation. J Clin Neurophysiol, 2010. 27(2): p. 130-138.PubMedCrossRefGoogle Scholar
  35. 35.
    Dunner, D.L., A.J. Rush, J.M. Russell, M. Burke, S. Woodard, et al., Prospective, long-term, multicenter study of the naturalistic outcomes of patients with treatment-resistant depression. J Clin Psychiatry, 2006. 67(5): p. 688-695.PubMedCrossRefGoogle Scholar
  36. 36.
    Freeman, M.P., D. Mischoulon, E. Tedeschini, T. Goodness, L.S. Cohen, et al., Complementary and alternative medicine for major depressive disorder: a meta-analysis of patient characteristics, placeboresponse rates, and treatment outcomes relative to standard antidepressants. J Clin Psychiatry, 2010. 71(6): p. 682-688.PubMedCrossRefGoogle Scholar
  37. 37.
    Khan, A., N. Redding, and W.A. Brown, The persistence of the placebo response in antidepressant clinical trials. J Psychiatr Res, 2008. 42(10): p. 791-796.PubMedCrossRefGoogle Scholar
  38. 38.
    Borges, S., Y.F. Chen, T.P. Laughren, R. Temple, H.D. Patel, et al., Review of maintenance trials for major depressive disorder: a 25-year perspective from the US Food and Drug Administration. J Clin Psychiatry, 2014. 75(3): p. 205-214.PubMedCrossRefGoogle Scholar
  39. 39.
    Undurraga, J. and R.J. Baldessarini, Randomized, placebo-controlled trials of antidepressants for acute major depression: thirty-year meta-analytic review. Neuropsychopharmacology, 2012. 37(4): p. 851-864.PubMedCrossRefGoogle Scholar
  40. 40.
    Rush, A.J., M.S. George, H.A. Sackeim, L.B. Marangell, M.M. Husain, et al., Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study. Biol Psychiatry, 2000. 47(4): p. 276-286.PubMedCrossRefGoogle Scholar
  41. 41.
    Sackeim, H.A., A.J. Rush, M.S. George, L.B. Marangell, M.M. Husain, et al., Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology, 2001. 25(5): p. 713-728.PubMedCrossRefGoogle Scholar
  42. 42.
    Rush, A.J., L.B. Marangell, H.A. Sackeim, M.S. George, S.K. Brannan, et al., Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol Psychiatry, 2005. 58(5): p. 347-354.PubMedCrossRefGoogle Scholar
  43. 43.
    Nahas, Z., L.B. Marangell, M.M. Husain, A.J. Rush, H.A. Sackeim, et al., Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J Clin Psychiatry, 2005. 66(9): p. 1097-1104.PubMedCrossRefGoogle Scholar
  44. 44.
    Sackeim, H.A., S.K. Brannan, A.J. Rush, M.S. George, L.B. Marangell, et al., Durability of antidepressant response to vagus nerve stimulation (VNS). Int J Neuropsychopharmacol, 2007. 10(6): p. 817-826.PubMedCrossRefGoogle Scholar
  45. 45.
    Coryell, W., H.S. Akiskal, A.C. Leon, G. Winokur, J.D. Maser, et al., The time course of nonchronic major depressive disorder. Uniformity across episodes and samples. National Institute of Mental Health Collaborative Program on the Psychobiology of Depression--Clinical Studies. Arch Gen Psychiatry, 1994. 51(5): p. 405-410.PubMedCrossRefGoogle Scholar
  46. 46.
    Eaton, W.W., H. Shao, G. Nestadt, H.B. Lee, O.J. Bienvenu, et al., Population-based study of first onset and chronicity in major depressive disorder. Arch Gen Psychiatry, 2008. 65(5): p. 513-520.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    George, M.S., A.J. Rush, L.B. Marangell, H.A. Sackeim, S.K. Brannan, et al., A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatry, 2005. 58(5): p. 364-373.PubMedCrossRefGoogle Scholar
  48. 48.
    Schlaepfer, T.E., C. Frick, A. Zobel, W. Maier, I. Heuser, et al., Vagus nerve stimulation for depression: efficacy and safety in a European study. Psychol Med, 2008. 38(5): p. 651-661.PubMedCrossRefGoogle Scholar
  49. 49.
    Bajbouj, M., A. Merkl, T.E. Schlaepfer, C. Frick, A. Zobel, et al., Two-year outcome of vagus nerve stimulation in treatment-resistant depression. J Clin Psychopharmacol, 2010. 30(3): p. 273-281.PubMedCrossRefGoogle Scholar
  50. 50.
    Christmas, D., J.D. Steele, S. Tolomeo, M.S. Eljamel, and K. Matthews, Vagus nerve stimulation for chronic major depressive disorder: 12-month outcomes in highly treatment-refractory patients. J Affect Disord, 2013. 150(3): p. 1221-1225.PubMedCrossRefGoogle Scholar
  51. 51.
    Aaronson, S.T., P. Sears, F. Ruvuna, M. Bunker, C.R. Conway, et al., A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality. Am J Psychiatry, 2017 Mar 31 [Epub ahead of print].Google Scholar
  52. 52.
    Feldman, R.L., D.L. Dunner, J.S. Muller, and D.A. Stone, Medicare patient experience with vagus nerve stimulation for treatment-resistant depression. J Med Econ, 2013. 16(1): p. 62-74.PubMedCrossRefGoogle Scholar
  53. 53.
    Peuker, E.T. and T.J. Filler, The nerve supply of the human auricle. Clin Anat, 2002. 15(1): p. 35-37.PubMedCrossRefGoogle Scholar
  54. 54.
    Fallgatter, A.J., B. Neuhauser, M.J. Herrmann, A.C. Ehlis, A. Wagener, et al., Far field potentials from the brain stem after transcutaneous vagus nerve stimulation. J Neural Transm (Vienna), 2003. 110(12): p. 1437-1443.CrossRefGoogle Scholar
  55. 55.
    Dietrich, S., J. Smith, C. Scherzinger, K. Hofmann-Preiss, T. Freitag, et al., [A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI]. Biomed Tech (Berl), 2008. 53(3): p. 104-111.Google Scholar
  56. 56.
    Kraus, T., K. Hosl, O. Kiess, A. Schanze, J. Kornhuber, et al., BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation. J Neural Transm (Vienna), 2007. 114(11): p. 1485-1493.CrossRefGoogle Scholar
  57. 57.
    Fang, J., P. Rong, Y. Hong, Y. Fan, J. Liu, et al., Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder. Biol Psychiatry, 2016. 79(4): p. 266-273.PubMedCrossRefGoogle Scholar
  58. 58.
    Liu, J., J. Fang, Z. Wang, P. Rong, Y. Hong, et al., Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression. J Affect Disord, 2016. 205: p. 319-326.PubMedCrossRefGoogle Scholar
  59. 59.
    Hein, E., M. Nowak, O. Kiess, T. Biermann, K. Bayerlein, et al., Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. J Neural Transm (Vienna), 2013. 120(5): p. 821-827.CrossRefGoogle Scholar
  60. 60.
    Rong, P., J. Liu, L. Wang, R. Liu, J. Fang, et al., Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study. J Affect Disord, 2016. 195: p. 172-179.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Bohning, D.E., M.P. Lomarev, S. Denslow, Z. Nahas, A. Shastri, et al., Feasibility of vagus nerve stimulation-synchronized blood oxygenation level-dependent functional MRI. Invest Radiol, 2001. 36(8): p. 470–479.PubMedCrossRefGoogle Scholar
  62. 62.
    Conway, C.R., J.T. Chibnall, M.A. Gebara, J.L. Price, A.Z. Snyder, et al., Association of cerebral metabolic activity changes with vagus nerve stimulation antidepressant response in treatment-resistant depression. Brain Stimul, 2013. 6(5): p. 788-797.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Mu, Q., D.E. Bohning, Z. Nahas, J. Walker, B. Anderson, et al., Acute vagus nerve stimulation using different pulse widths produces varying brain effects. Biol Psychiatry, 2004. 55(8): p. 816-825.PubMedCrossRefGoogle Scholar
  64. 64.
    Nahas, Z., C. Teneback, J.H. Chae, Q. Mu, C. Molnar, et al., Serial vagus nerve stimulation functional MRI in treatment-resistant depression. Neuropsychopharmacology, 2007. 32(8): p. 1649-1660.PubMedCrossRefGoogle Scholar
  65. 65.
    Chae, J.H., Z. Nahas, M. Lomarev, S. Denslow, J.P. Lorberbaum, et al., A review of functional neuroimaging studies of vagus nerve stimulation (VNS). J Psychiatr Res, 2003. 37(6): p. 443-455.PubMedCrossRefGoogle Scholar
  66. 66.
    Conway, C.R., Y.I. Sheline, J.T. Chibnall, R.D. Bucholz, J.L. Price, et al., Brain blood-flow change with acute vagus nerve stimulation in treatment-refractory major depressive disorder. Brain Stimul, 2012. 5(2): p. 163-171.PubMedCrossRefGoogle Scholar
  67. 67.
    Kosel, M., H. Brockmann, C. Frick, A. Zobel, and T.E. Schlaepfer, Chronic vagus nerve stimulation for treatment-resistant depression increases regional cerebral blood flow in the dorsolateral prefrontal cortex. Psychiatry Res, 2011. 191(3): p. 153-159.PubMedCrossRefGoogle Scholar
  68. 68.
    Frangos, E., J. Ellrich, and B.R. Komisaruk, Non-invasive Access to the Vagus Nerve Central Projections via Electrical Stimulation of the External Ear: fMRI Evidence in Humans. Brain Stimul, 2015. 8(3): p. 624-636.PubMedCrossRefGoogle Scholar
  69. 69.
    Fang, J., N. Egorova, P. Rong, J. Liu, Y. Hong, et al., Early cortical biomarkers of longitudinal transcutaneous vagus nerve stimulation treatment success in depression. Neuroimage Clin, 2017. 14: p. 105-111.PubMedCrossRefGoogle Scholar
  70. 70.
    Yakunina, N., S.S. Kim, and E.C. Nam, Optimization of Transcutaneous Vagus Nerve Stimulation Using Functional MRI. Neuromodulation, 2017. 20(3): p. 290-300.PubMedCrossRefGoogle Scholar
  71. 71.
    Cunningham, J.T., S.W. Mifflin, G.G. Gould, and A. Frazer, Induction of c-Fos and DeltaFosB immunoreactivity in rat brain by Vagal nerve stimulation. Neuropsychopharmacology, 2008. 33(8): p. 1884-1895.PubMedCrossRefGoogle Scholar
  72. 72.
    Furmaga, H., M. Sadhu, and A. Frazer, Comparison of DeltaFosB immunoreactivity induced by vagal nerve stimulation with that caused by pharmacologically diverse antidepressants. J Pharmacol Exp Ther, 2012. 341(2): p. 317-325.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Naritoku, D.K., W.J. Terry, and R.H. Helfert, Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. Epilepsy Res, 1995. 22(1): p. 53-62.PubMedCrossRefGoogle Scholar
  74. 74.
    Kovacs, K.J., c-Fos as a transcription factor: a stressful (re)view from a functional map. Neurochem Int, 1998. 33(4): p. 287-297.PubMedCrossRefGoogle Scholar
  75. 75.
    Chen, J., M.B. Kelz, B.T. Hope, Y. Nakabeppu, and E.J. Nestler, Chronic Fos-related antigens: stable variants of deltaFosB induced in brain by chronic treatments. J Neurosci, 1997. 17(13): p. 4933-4941.PubMedGoogle Scholar
  76. 76.
    Nestler, E.J., Molecular mechanisms of drug addiction. Neuropharmacology, 2004. 47 Suppl 1: p. 24-32.PubMedCrossRefGoogle Scholar
  77. 77.
    Engineer, C.T., N.D. Engineer, J.R. Riley, J.D. Seale, and M.P. Kilgard, Pairing Speech Sounds With Vagus Nerve Stimulation Drives Stimulus-specific Cortical Plasticity. Brain Stimul, 2015. 8(3): p. 637-644.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Hays, S.A., R.L. Rennaker, and M.P. Kilgard, Targeting plasticity with vagus nerve stimulation to treat neurological disease. Prog Brain Res, 2013. 207: p. 275-299.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Shetake, J.A., N.D. Engineer, W.A. Vrana, J.T. Wolf, and M.P. Kilgard, Pairing tone trains with vagus nerve stimulation induces temporal plasticity in auditory cortex. Exp Neurol, 2012. 233(1): p. 342-349.PubMedCrossRefGoogle Scholar
  80. 80.
    Khodaparast, N., S.A. Hays, A.M. Sloan, T. Fayyaz, D.R. Hulsey, et al., Vagus nerve stimulation delivered during motor rehabilitation improves recovery in a rat model of stroke. Neurorehabil Neural Repair, 2014. 28(7): p. 698-706.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Khodaparast, N., S.A. Hays, A.M. Sloan, D.R. Hulsey, A. Ruiz, et al., Vagus nerve stimulation during rehabilitative training improves forelimb strength following ischemic stroke. Neurobiol Dis, 2013. 60: p. 80-88.PubMedCrossRefGoogle Scholar
  82. 82.
    Childs, J.E., J. DeLeon, E. Nickel, and S. Kroener, Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network. Learn Mem, 2017. 24(1): p. 35-42.PubMedCrossRefGoogle Scholar
  83. 83.
    Oshinsky, M.L., A.L. Murphy, H. Hekierski, Jr., M. Cooper, and B.J. Simon, Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain, 2014. 155(5): p. 1037-1042.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Pavlov, V.A. and K.J. Tracey, The vagus nerve and the inflammatory reflex--linking immunity and metabolism. Nat Rev Endocrinol, 2012. 8(12): p. 743-754.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Das, U.N., Is depression a low-grade systemic inflammatory condition? Am J Clin Nutr, 2007. 85(6): p. 1665-1666.PubMedGoogle Scholar
  86. 86.
    Corcoran, C., T.J. Connor, V. O'Keane, and M.R. Garland, The effects of vagus nerve stimulation on proand anti-inflammatory cytokines in humans: a preliminary report. Neuroimmunomodulation, 2005. 12(5): p. 307-309.PubMedCrossRefGoogle Scholar
  87. 87.
    Levine, J., Y. Barak, K.N. Chengappa, A. Rapoport, M. Rebey, et al., Cerebrospinal cytokine levels in patients with acute depression. Neuropsychobiology, 1999. 40(4): p. 171-176.PubMedCrossRefGoogle Scholar
  88. 88.
    Suarez, E.C., R.R. Krishnan, and J.G. Lewis, The relation of severity of depressive symptoms to monocyte-associated proinflammatory cytokines and chemokines in apparently healthy men. Psychosom Med, 2003. 65(3): p. 362-368.PubMedCrossRefGoogle Scholar
  89. 89.
    Lindqvist, D., S. Janelidze, P. Hagell, S. Erhardt, M. Samuelsson, et al., Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity. Biol Psychiatry, 2009. 66(3): p. 287-292.PubMedCrossRefGoogle Scholar
  90. 90.
    Koopman, F.A., S.S. Chavan, S. Miljko, S. Grazio, S. Sokolovic, et al., Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A, 2016. 113(29): p. 8284-8289.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Delgado, P.L., D.S. Charney, L.H. Price, G.K. Aghajanian, H. Landis, et al., Serotonin function and the mechanism of antidepressant action. Reversal of antidepressant-induced remission by rapid depletion of plasma tryptophan. Arch Gen Psychiatry, 1990. 47(5): p. 411-418.PubMedCrossRefGoogle Scholar
  92. 92.
    Gyermek, L., The pharmacology of imipramine and related antidepressants. Int Rev Neurobiol, 1966. 9: p. 95-143.PubMedCrossRefGoogle Scholar
  93. 93.
    Heninger, G.R., P.L. Delgado, and D.S. Charney, The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry, 1996. 29(1): p. 2-11.PubMedCrossRefGoogle Scholar
  94. 94.
    Prange, A.J., Jr., The Pharmacology and Biochemistry of Depression. Dis Nerv Syst, 1964. 25: p. 217-221.PubMedGoogle Scholar
  95. 95.
    Schildkraut, J.J., The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry, 1965. 122(5): p. 509-522.PubMedCrossRefGoogle Scholar
  96. 96.
    Manta, S., J. Dong, G. Debonnel, and P. Blier, Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation. J Psychiatry Neurosci, 2009. 34(4): p. 272-280.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Landau, A.M., S. Dyve, S. Jakobsen, A.K. Alstrup, A. Gjedde, et al., Acute Vagal Nerve Stimulation Lowers alpha2 Adrenoceptor Availability: Possible Mechanism of Therapeutic Action. Brain Stimul, 2015. 8(4): p. 702-707.PubMedCrossRefGoogle Scholar
  98. 98.
    Follesa, P., F. Biggio, G. Gorini, S. Caria, G. Talani, et al., Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain. Brain Res, 2007. 1179: p. 28-34.PubMedCrossRefGoogle Scholar
  99. 99.
    Hassert, D.L., T. Miyashita, and C.L. Williams, The effects of peripheral vagal nerve stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala. Behav Neurosci, 2004. 118(1): p. 79-88.PubMedCrossRefGoogle Scholar
  100. 100.
    Roosevelt, R.W., D.C. Smith, R.W. Clough, R.A. Jensen, and R.A. Browning, Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat. Brain Res, 2006. 1119(1): p. 124-132.Google Scholar
  101. 101.
    Manta, S., M. El Mansari, G. Debonnel, and P. Blier, Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems. Int J Neuropsychopharmacol, 2013. 16(2): p. 459-470.PubMedCrossRefGoogle Scholar
  102. 102.
    Perez, S.M., F.R. Carreno, A. Frazer, and D.J. Lodge, Vagal nerve stimulation reverses aberrant dopamine system function in the methylazoxymethanol acetate rodent model of schizophrenia. J Neurosci, 2014. 34(28): p. 9261-9267.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Lodge, D.J., The MAM rodent model of schizophrenia. Curr Protoc Neurosci, 2013. Chapter 9: p. Unit9 43.Google Scholar
  104. 104.
    Moore, H., J.D. Jentsch, M. Ghajarnia, M.A. Geyer, and A.A. Grace, A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol Psychiatry, 2006. 60(3): p. 253-264.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Hasan, A., C. Wolff-Menzler, S. Pfeiffer, P. Falkai, E. Weidinger, et al., Transcutaneous noninvasive vagus nerve stimulation (tVNS) in the treatment of schizophrenia: a bicentric randomized controlled pilot study. Eur Arch Psychiatry Clin Neurosci, 2015. 265(7): p. 589-600.PubMedCrossRefGoogle Scholar
  106. 106.
    Porsolt, R.D., A. Bertin, and M. Jalfre, Behavioral despair in mice: a primary screening test for antidepressants. Arch Int Pharmacodyn Ther, 1977. 229(2): p. 327-336.PubMedGoogle Scholar
  107. 107.
    Bodnoff, S.R., B. Suranyi-Cadotte, D.H. Aitken, R. Quirion, and M.J. Meaney, The effects of chronic antidepressant treatment in an animal model of anxiety. Psychopharmacology (Berl), 1988. 95(3): p. 298-302.CrossRefGoogle Scholar
  108. 108.
    Furmaga, H., A. Shah, and A. Frazer, Serotonergic and noradrenergic pathways are required for the anxiolytic-like and antidepressant-like behavioral effects of repeated vagal nerve stimulation in rats. Biol Psychiatry, 2011. 70(10): p. 937-945.PubMedCrossRefGoogle Scholar
  109. 109.
    Krahl, S.E., S.S. Senanayake, A.E. Pekary, and A. Sattin, Vagus nerve stimulation (VNS) is effective in a rat model of antidepressant action. J Psychiatr Res, 2004. 38(3): p. 237-240.PubMedCrossRefGoogle Scholar
  110. 110.
    Grimonprez, A., R. Raedt, C. Baeken, P. Boon, and K. Vonck, The antidepressant mechanism of action of vagus nerve stimulation: Evidence from preclinical studies. Neurosci Biobehav Rev, 2015. 56: p. 26-34.PubMedCrossRefGoogle Scholar
  111. 111.
    Duman, R.S., J. Malberg, and S. Nakagawa, Regulation of adult neurogenesis by psychotropic drugs and stress. J Pharmacol Exp Ther, 2001. 299(2): p. 401-407.PubMedGoogle Scholar
  112. 112.
    Duman, R.S., S. Nakagawa, and J. Malberg, Regulation of adult neurogenesis by antidepressant treatment. Neuropsychopharmacology, 2001. 25(6): p. 836-844.PubMedCrossRefGoogle Scholar
  113. 113.
    Jacobs, B.L., H. van Praag, and F.H. Gage, Adult brain neurogenesis and psychiatry: a novel theory of depression. Mol Psychiatry, 2000. 5(3): p. 262-269.PubMedCrossRefGoogle Scholar
  114. 114.
    Biggio, F., G. Gorini, C. Utzeri, P. Olla, F. Marrosu, et al., Chronic vagus nerve stimulation induces neuronal plasticity in the rat hippocampus. Int J Neuropsychopharmacol, 2009. 12(9): p. 1209-2021.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Revesz, D., M. Tjernstrom, E. Ben-Menachem, and T. Thorlin, Effects of vagus nerve stimulation on rat hippocampal progenitor proliferation. Exp Neurol, 2008. 214(2): p. 259-265.PubMedCrossRefGoogle Scholar
  116. 116.
    Gebhardt, N., K.J. Bar, M.K. Boettger, G. Grecksch, G. Keilhoff, et al., Vagus nerve stimulation ameliorated deficits in one-way active avoidance learning and stimulated hippocampal neurogenesis in bulbectomized rats. Brain Stimul, 2013. 6(1): p. 78-83.PubMedCrossRefGoogle Scholar
  117. 117.
    Madsen, T.M., S.S. Newton, M.E. Eaton, D.S. Russell, and R.S. Duman, Chronic electroconvulsive seizure up-regulates beta-catenin expression in rat hippocampus: role in adult neurogenesis. Biol Psychiatry, 2003. 54(10): p. 1006-1014.PubMedCrossRefGoogle Scholar
  118. 118.
    Hanson, N.D., C.B. Nemeroff, and M.J. Owens, Lithium, but not fluoxetine or the corticotropin-releasing factor receptor 1 receptor antagonist R121919, increases cell proliferation in the adult dentate gyrus. J Pharmacol Exp Ther, 2011. 337(1): p. 180-186.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Santarelli, L., M. Saxe, C. Gross, A. Surget, F. Battaglia, et al., Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science, 2003. 301(5634): p. 805-809.PubMedCrossRefGoogle Scholar
  120. 120.
    Wainwright, S.R. and L.A. Galea, The neural plasticity theory of depression: assessing the roles of adult neurogenesis and PSA-NCAM within the hippocampus. Neural Plast, 2013. 2013: p. 805497.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Warner-Schmidt, J.L. and R.S. Duman, Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment. Hippocampus, 2006. 16(3): p. 239-249.PubMedCrossRefGoogle Scholar
  122. 122.
    Couillard-Despres, S., B. Iglseder, and L. Aigner, Neurogenesis, cellular plasticity and cognition: the impact of stem cells in the adult and aging brain--a mini-review. Gerontology, 2011. 57(6): p. 559-564.PubMedCrossRefGoogle Scholar
  123. 123.
    Couillard-Despres, S., B. Winner, S. Schaubeck, R. Aigner, M. Vroemen, et al., Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci, 2005. 21(1): p. 1-14.Google Scholar
  124. 124.
    Wang, J.W., D.J. David, J.E. Monckton, F. Battaglia, and R. Hen, Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci, 2008. 28(6): p. 1374-1384.PubMedCrossRefGoogle Scholar
  125. 125.
    Yuan, T.F., A. Li, X. Sun, O. Arias-Carrion, and S. Machado, Vagus nerve stimulation in treating depression: A tale of two stories. Curr Mol Med, 2016. 16(1): p. 33-39.PubMedCrossRefGoogle Scholar
  126. 126.
    Duman, R.S. and L.M. Monteggia, A neurotrophic model for stress-related mood disorders. Biol Psychiatry, 2006. 59(12): p. 1116-1127.PubMedCrossRefGoogle Scholar
  127. 127.
    Nibuya, M., S. Morinobu, and R.S. Duman, Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci, 1995. 15(11): p. 7539-7547.PubMedGoogle Scholar
  128. 128.
    Nibuya, M., E.J. Nestler, and R.S. Duman, Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci, 1996. 16(7): p. 2365-2372.PubMedGoogle Scholar
  129. 129.
    Furmaga, H., F.R. Carreno, and A. Frazer, Vagal nerve stimulation rapidly activates brain-derived neurotrophic factor receptor TrkB in rat brain. PLoS ONE, 2012. 7(5): p. e34844.Google Scholar
  130. 130.
    Shah, A.P., F.R. Carreno, H. Wu, Y.A. Chung, and A. Frazer, Role of TrkB in the anxiolytic-like and antidepressant-like effects of vagal nerve stimulation: Comparison with desipramine. Neuroscience, 2016. 322: p. 273-286.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Rantamaki, T., P. Hendolin, A. Kankaanpaa, J. Mijatovic, P. Piepponen, et al., Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacology, 2007. 32(10): p. 2152-2162.PubMedCrossRefGoogle Scholar
  132. 132.
    Saarelainen, T., P. Hendolin, G. Lucas, E. Koponen, M. Sairanen, et al., Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci, 2003. 23(1): p. 349-357.PubMedGoogle Scholar
  133. 133.
    Carreno, F.R. and A. Frazer, Activation of signaling pathways downstream of the brain-derived neurotrophic factor receptor, TrkB, in the rat brain by vagal nerve stimulation and antidepressant drugs. Int J Neuropsychopharmacol, 2014. 17(2): p. 247-258.PubMedCrossRefGoogle Scholar
  134. 134.
    Li, S., X. Zhai, P. Rong, M.F. McCabe, J. Zhao, et al., Transcutaneous auricular vagus nerve stimulation triggers melatonin secretion and is antidepressive in Zucker diabetic fatty rats. PLoS One, 2014. 9(10): p. e111100.Google Scholar
  135. 135.
    Liu, R.P., J.L. Fang, P.J. Rong, Y. Zhao, H. Meng, et al., Effects of electroacupuncture at auricular concha region on the depressive status of unpredictable chronic mild stress rat models. Evid Based Complement Alternat Med, 2013. 2013: p. 789674.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Kitamura, Y., K. Akiyama, S. Hashimoto, K. Kitagawa, H. Kawasaki, et al., Effects of imipramine on extracellular serotonin and noradrenaline concentrations in ACTH-treated rats. Eur J Pharmacol, 2007. 566(1-3): p. 113-116.PubMedCrossRefGoogle Scholar
  137. 137.
    Kitamura, Y., K. Akiyama, K. Kitagawa, K. Shibata, H. Kawasaki, et al., Chronic coadministration of carbamazepine together with imipramine produces antidepressant-like effects in an ACTH-induced animal model of treatment-resistant depression: involvement of 5-HT(2A) receptors? Pharmacol Biochem Behav, 2008. 89(3): p. 235-240.PubMedCrossRefGoogle Scholar
  138. 138.
    Kitamura, Y., H. Araki, and Y. Gomita, Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test. Pharmacol Biochem Behav, 2002. 71(1-2): p. 63-69.PubMedCrossRefGoogle Scholar
  139. 139.
    O'Leary, O.F., S. Zandy, T.G. Dinan, and J.F. Cryan, Lithium augmentation of the effects of desipramine in a mouse model of treatment-resistant depression: a role for hippocampal cell proliferation. Neuroscience, 2013. 228: p. 36-46.PubMedCrossRefGoogle Scholar
  140. 140.
    Winter, C., B. Vollmayr, A. Djodari-Irani, J. Klein, and A. Sartorius, Pharmacological inhibition of the lateral habenula improves depressive-like behavior in an animal model of treatment resistant depression. Behav Brain Res, 2011. 216(1): p. 463-465.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  1. 1.Department of PharmacologyUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  2. 2.Center for Biomedical NeuroscienceUniversity of Texas Health Science Center at San AntonioSan AntonioUSA
  3. 3.South Texas Veterans Health Care SystemSan AntonioUSA

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