Deep Brain Stimulation of the Human Reward System as a Putative Treatment for Refractory Major Depression

  • T. E. Schlaepfer
  • V. A. Coenen
  • B. H. Bewernick


Several brain structures play a germane role in the development and maintenance of symptoms in depression. Current studies in treatment-resistant depression (TRD) are targeting the nucleus accumbens (NAc), the medial forebrain bundle, the anterior cingulate cortex (Cg25), and the anterior limb of the internal capsule. The NAc has been studied as a target site for deep brain stimulation (DBS) in depression because of its prominent role in the reward system. The first evidence on a small sample studied for up to 4 years has proven that NAc DBS induces stable, sustained antidepressant effects in 50 % of patients. It is not yet possible to decide on the optimal target for DBS in TRD: the studies are small, long-term data are only available for up to 5 years, and the stimulation amplitude is high compared with neurological indications. The medial forebrain bundle—connecting frontal DBS targets (Cg25) with the NAc—has recently been proposed as new hypothesis-driven target awaiting clinical evidence. The application of NAc DBS for the treatment of bipolar disorder and other psychiatric diseases (e.g., alcohol dependency, opioid addiction, schizophrenia) is currently being investigated. No fundamental ethical objections to the use of DBS in psychiatric disorders have been put forward, but until substantial clinical data are available, mandatory standards are needed to prevent harming patients.


Deep Brain Stimulation Antidepressant Effect Ventral Striatum Medial Forebrain Bundle Fiber Tracking 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Adinoff B (2004) Neurobiologic processes in drug reward and addiction. Harv Rev Psychiatry 12(6):305–320PubMedCrossRefGoogle Scholar
  2. Aharon I, Etcoff N et al (2001) Beautiful faces have variable reward value: fMRI and behavioral evidence. Neuron 32(3):537–551PubMedCrossRefGoogle Scholar
  3. American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Association, ArlingtonGoogle Scholar
  4. Argyropoulos SV, Nutt DJ (1997) Anhedonia and chronic mild stress model in depression. Psychopharmacology (Berl) 134(4):333–336; discussion 371–337Google Scholar
  5. Belmaker RH (2004) Bipolar disorder. N Engl J Med 351(5):476–486PubMedCrossRefGoogle Scholar
  6. Berns GS, Nemeroff CB (2003) The neurobiology of bipolar disorder. Am J Med Genet C Semin Med Genet 123(1):76–84CrossRefGoogle Scholar
  7. Berton O, Nestler EJ (2006) New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci 7(2):137–151PubMedCrossRefGoogle Scholar
  8. Bewernick BH, Hurlemann R et al (2010) Nucleus accumbens deep brain stimulationdeep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry 67(2):110–116PubMedCrossRefGoogle Scholar
  9. Bewernick B, Kayser S et al. (2012) Long-term effects of nucleus accumbens deep brain stimulation in treatment resistant depression—evidence for sustained efficacy. Neuropsychopharmacology (in press)Google Scholar
  10. Breiter HC, Gollub RL et al (1997) Acute effects of cocaine on human brain activity and emotion. Neuron 19(3):591–611PubMedCrossRefGoogle Scholar
  11. Coenen VA, Honey CR et al (2009) Medial forebrain bundle stimulation as a pathophysiological mechanism for hypomania in subthalamic nucleussubthalamic nucleus deep brain stimulationdeep brain stimulation for Parkinson’s disease. Neurosurgery 64(6):1106–1114; discussion 1114–1105Google Scholar
  12. Coenen VA, Schlaepfer TE et al (2011) Cross-species affective functions of the medial forebrain bundle–implications for the treatment of affective pain and depression in humans. Neurosci Biobehav Rev 35(9):1971–1981PubMedCrossRefGoogle Scholar
  13. Cohen MX, Young J et al (2005) Individual differences in extraversion and dopamine genetics predict neural reward responses. Brain Res Cogn Brain Res 25(3):851–861PubMedCrossRefGoogle Scholar
  14. de la Fuente-Fernandez R, Phillips AG et al (2002) Dopamine release in human ventral striatum and expectation of reward. Behav Brain Res 136(2):359–363PubMedCrossRefGoogle Scholar
  15. Doyon WM, Anders SK et al (2005) Effect of operant self-administration of 10 % ethanol plus 10 % sucrose on dopamine and ethanol concentrations in the nucleus accumbens. J Neurochem 93(6):1469–1481PubMedCrossRefGoogle Scholar
  16. Drevets WC, Gautier C et al (2001) Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biol Psychiatry 49(2):81–96PubMedCrossRefGoogle Scholar
  17. Gijsman HJ, Geddes JR et al (2004) Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry 161(9):1537–1547PubMedCrossRefGoogle Scholar
  18. Gradinaru V, Mogri M et al (2009) Optical deconstruction of parkinsonian neural circuitry. Science 324(5925):354–359PubMedCrossRefGoogle Scholar
  19. Grubert C, Hurlemann R et al (2011) Neuropsychological safety of nucleus accumbens deep brain stimulationdeep brain stimulation for major depression: effects of 12-month stimulation. World J Biol Psychiatry 12(7):516–527PubMedCrossRefGoogle Scholar
  20. Gutman DA, Holtzheimer PE et al (2009) A tractography analysis of two deep brain stimulationdeep brain stimulation white matter targets for depression. Biol Psychiatry 65(4):276–282PubMedCrossRefGoogle Scholar
  21. Hamani C, Mayberg H et al (2009) Deep brain stimulation of the subcallosal cingulate gyrus for depression: anatomical location of active contacts in clinical responders and a suggested guideline for targeting. J Neurosurg 111(6):1209–1215PubMedCrossRefGoogle Scholar
  22. Hamani C, Nobrega JN (2010) Deep brain stimulation in clinical trials and animal models of depression. Eur J Neurosci 32(7):1109–1117PubMedCrossRefGoogle Scholar
  23. Haq IU, Foote KD et al (2010) A case of mania following deep brain stimulationdeep brain stimulation for obsessive compulsive disorderobsessive compulsive disorder. Stereotact Funct Neurosurg 88(5):322–328PubMedCrossRefGoogle Scholar
  24. Huff W, Lenartz D et al (2010) Unilateral deep brain stimulationdeep brain stimulation of the nucleus accumbens in patients with treatment-resistant obsessive-compulsive disorder: outcomes after one year. Clin Neurol Neurosurg 112(2):137–143PubMedCrossRefGoogle Scholar
  25. Ito R, Robbins TW et al (2004) Differential control over cocaine-seeking behavior by nucleus accumbens core and shell. Nat Neurosci 7(4):389–397PubMedCrossRefGoogle Scholar
  26. Johansen-Berg H, Gutman DA et al (2008) Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulationdeep brain stimulation for treatment-resistant depression. Cereb Cortex 18(6):1374–1383PubMedCrossRefGoogle Scholar
  27. Jones DL, Mogenson GJ (1980) Nucleus accumbens to globus pallidus GABA projection: electrophysiological and iontophoretic investigations. Brain Res 188(1):93–105PubMedCrossRefGoogle Scholar
  28. Juckel G, Schlagenhauf F et al (2006) Dysfunction of ventral striatal reward prediction in schizophrenia. Neuroimage 29(2):409–416PubMedCrossRefGoogle Scholar
  29. Kelley AE, Stinus L (1984) The distribution of the projection from the parataenial nucleus of the thalamus to the nucleus accumbens in the rat: an autoradiographic study. Exp Brain Res 54(3):499–512PubMedCrossRefGoogle Scholar
  30. Kennedy SH, Giacobbe P et al (2011) Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. Am J Psychiatry 168(5):502–510PubMedCrossRefGoogle Scholar
  31. Klein J, Soto-Montenegro ML et al (2011) A novel approach to investigate neuronal network activity patterns affected by deep brain stimulationdeep brain stimulation in rats. J Psychiatr Res 45(7):927–930PubMedCrossRefGoogle Scholar
  32. Knutson B, Adams CM et al (2001) Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci 21(16):RC159Google Scholar
  33. Knutson B, Fong GW et al (2003) A region of mesial prefrontal cortexprefrontal cortex tracks monetarily rewarding outcomes: characterization with rapid event-related fMRI. Neuroimage 18(2):263–272PubMedCrossRefGoogle Scholar
  34. Kuhn J, Bauer R et al (2009) Observations on unaided smoking cessation after deep brain stimulationdeep brain stimulation of the nucleus accumbens. Eur Addict Res 15(4):196–201PubMedCrossRefGoogle Scholar
  35. Kuhn J, Lenartz D et al (2007) Remission of alcohol dependency following deep brain stimulationdeep brain stimulation of the nucleus accumbens: valuable therapeutic implications? J Neurol Neurosurg Psychiatry 78(10):1152–1153.PubMedCrossRefGoogle Scholar
  36. Kupferschmidt DA, Zakzanis KK (2011) Toward a functional neuroanatomical signature of bipolar disorder: quantitative evidence from the neuroimaging literature. Psychiatry Res 193(2):71–79PubMedCrossRefGoogle Scholar
  37. Loas G (1996) Vulnerability to depression: a model centered on anhedonia. J Affect Disord 41(1):39–53PubMedCrossRefGoogle Scholar
  38. Lozano AM, Mayberg HS et al (2008) Subcallosal cingulate gyrus deep brain stimulationdeep brain stimulation for treatment-resistant depression. Biol Psychiatry 64(6):461–467PubMedCrossRefGoogle Scholar
  39. Malone DA Jr, Dougherty DD et al (2009) Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry 65(4):267–275PubMedCrossRefGoogle Scholar
  40. Marchand WR, Yurgelun-Todd D (2010) Striatal structure and function in mood disorders: a comprehensive review. Bipolar Disord 12(8):764–785PubMedCrossRefGoogle Scholar
  41. Mayberg H, Lozano A et al (2005) Deep brain stimulation for treatment-resistant depression. Neuron 45(5):651–660PubMedCrossRefGoogle Scholar
  42. Mayberg HS (1997) Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci 9(3):471–481PubMedGoogle Scholar
  43. Mogenson GJ, Swanson LW et al (1983) Neural projections from nucleus accumbens to globus pallidus, substantia innominata, and lateral preoptic-lateral hypothalamic area: an anatomical and electrophysiological investigation in the rat. J Neurosci 3(1):189–202PubMedGoogle Scholar
  44. Nauta WJ, Domesick VB (1984) Afferent and efferent relationships of the basal gangliabasal ganglia. Ciba Found Symp 107:3–29PubMedGoogle Scholar
  45. Nitschke JB, Sarinopoulos I et al (2009) Anticipatory activation in the amygdala and anterior cingulate in generalized anxiety disorder and prediction of treatment response. Am J Psychiatry 166(3):302–310PubMedCrossRefGoogle Scholar
  46. Nuttin B, Gybels J et al (2002) Deep brain stimulation for psychiatric disorders. Neurosurgery 51(2):519Google Scholar
  47. O’Doherty J, Kringelbach ML et al (2001) Abstract reward and punishment representations in the human orbitofrontal cortex. Nat Neurosci 4(1):95–102PubMedCrossRefGoogle Scholar
  48. Papadimitriou GN, Dikeos DG et al (2007) Non-pharmacological treatments in the management of rapid cycling bipolar disorder. J Affect Disord 98(1–2):1–10PubMedCrossRefGoogle Scholar
  49. Puigdemont D, Perez-Egea R et al (2011) Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression. Int J Neuropsychopharmacol:1–13Google Scholar
  50. Rush AJ, Weissenburger JE (1994) Melancholic symptom features and DSM-IV. Am J Psychiatry 151(4):489–498PubMedGoogle Scholar
  51. Sartorius A, Henn FA (2007) Deep brain stimulation of the lateral habenula in treatment resistant major depression. Med Hypotheses 69(6):1305–1308PubMedCrossRefGoogle Scholar
  52. Sartorius A, Kiening KL et al (2010) Remission of major depression under deep brain stimulationdeep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry 67(2):e9–e11PubMedCrossRefGoogle Scholar
  53. Schlaepfer TE, Lieb K (2005) Deep brain stimulation for treatment of refractory depression. Lancet 366(9495):1420–1422PubMedCrossRefGoogle Scholar
  54. Schlaepfer TE, Cohen MX et al (2008) Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 33(2):368–377PubMedCrossRefGoogle Scholar
  55. Schoene-Bake JC, Parpaley Y et al (2010) Tractographic analysis of historical lesion surgery for depression. Neuropsychopharmacology 35(13):2553–2563PubMedCrossRefGoogle Scholar
  56. Schultz W (2004) Neural coding of basic reward terms of animal learning theory, game theory, microeconomics and behavioural ecology. Curr Opin Neurobiol 14(2):139–147PubMedCrossRefGoogle Scholar
  57. Sturm V, Lenartz D et al (2003) The nucleus accumbens: a target for deep brain stimulationdeep brain stimulation in obsessive-compulsive- and anxiety-disorders. J Chem Neuroanat 26(4):293–299PubMedCrossRefGoogle Scholar
  58. Tremblay LK, Naranjo CA et al (2005) Functional neuroanatomical substrates of altered reward processing in major depressive disorder revealed by a dopaminergic probe. Arch Gen Psychiatry 62(11):1228–1236PubMedCrossRefGoogle Scholar
  59. Wise RA (1996) Addictive drugs and brain stimulation reward. Annu Rev Neurosci 19:319–340PubMedCrossRefGoogle Scholar
  60. Wolf DH (2006) Anhedonia in schizophrenia. Curr Psychiatry Rep 8(4):322–328PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • T. E. Schlaepfer
    • 1
    • 2
  • V. A. Coenen
    • 3
  • B. H. Bewernick
    • 1
  1. 1.Brain Stimulation Group, Department of Psychiatry and PsychotherapyUniversity Hospital BonnBonnGermany
  2. 2.Departments of Psychiatry and Mental HealthThe Johns Hopkins UniversityBaltimoreUSA
  3. 3.Department of Functional NeurosurgeryUniversity Hospital BonnBonnGermany

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