Deep Brain Stimulation in Animal Models of Depression

  • Brian W. Scott
  • José N. Nobrega
  • Clement HamaniEmail author


Deep brain stimulation (DBS) involves the delivery of electrical current to a specific brain site through chronically implanted electrodes. The procedure has shown promising results in investigational clinical trials to treat depression. Studies in animal models have recently been conducted to explore potential mechanisms and the substrates involved in the antidepressant-like effects of DBS. In this chapter, we review such studies and highlight some of the basic concepts for conducting preclinical research using DBS.


Deep brain stimulation Depression Animal models Preclinical studies 


Acknowledgments and Conflicts of Interest

Experimental work conducted by the authors has been supported in part by funds from the Brain & Behavior Research Foundation (NARSAD), the Ontario Mental Health Foundation, and the Canadian Institutes for Health Research. C.H. is a consultant to St. Jude Medical.


  1. Altar CA, Whitehead RE, Chen R, Wortwein G, Madsen TM (2003) Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 54:703–709PubMedCrossRefGoogle Scholar
  2. Banasr M, Duman RS (2008) Glial loss in the prefrontal cortex is sufficient to induce depressive-like behaviors. Biol Psychiatry 64:863–870PubMedCrossRefGoogle Scholar
  3. Banasr M, Valentine GW, Li XY, Gourley SL, Taylor JR, Duman RS (2007) Chronic unpredictable stress decreases cell proliferation in the cerebral cortex of the adult rat. Biol Psychiatry 62:496–504PubMedCrossRefGoogle Scholar
  4. Banasr M, Chowdhury GM, Terwilliger R, Newton SS, Duman RS, Behar KL et al (2010) Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Mol Psychiatry 15:501–511PubMedCrossRefGoogle Scholar
  5. Basar K, Sesia T, Groenewegen H, Steinbusch HW, Visser-Vandewalle V, Temel Y (2010) Nucleus accumbens and impulsivity. Prog Neurobiol 92:533–557PubMedCrossRefGoogle Scholar
  6. Bewernick BH, Hurlemann R, Matusch A, Kayser S, Grubert C, Hadrysiewicz B et al (2010) Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry 67:110–116PubMedCrossRefGoogle Scholar
  7. Cryan JF, Valentino RJ, Lucki I (2005) Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test. Neurosci Biobehav Rev 29:547–569PubMedCrossRefGoogle Scholar
  8. Depression Guideline Panel (1993a) Depression in primary care: vol 1 detection and diagnosis (Clinical Guideline No 5, AHCPR Publication No 93-0550). US: Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, RockvilleGoogle Scholar
  9. Depression Guideline Panel (1993b) Depression in primary care: vol 2 treatment of major depression (Clinical Guideline No 5, AHCPR Publication No 93-0551). US: Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, RockvilleGoogle Scholar
  10. Detke MJ, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology (Berl) 121:66–72CrossRefGoogle Scholar
  11. Friedman A, Frankel M, Flaumenhaft Y, Merenlender A, Pinhasov A, Feder Y et al (2009) Programmed acute electrical stimulation of ventral tegmental area alleviates depressive-like behavior. Neuropsychopharmacology 34:1057–1066PubMedCrossRefGoogle Scholar
  12. Friedman A, Lax E, Dikshtein Y, Abraham L, Flaumenhaft Y, Sudai E et al (2010) Electrical stimulation of the lateral habenula produces enduring inhibitory effect on cocaine seeking behavior. Neuropharmacology 59:452–459PubMedCrossRefGoogle Scholar
  13. Friedman A, Lax E, Dikshtein Y, Abraham L, Flaumenhaft Y, Sudai E et al (2011) Electrical stimulation of the lateral habenula produces an inhibitory effect on sucrose self-administration. Neuropharmacology 60:381–387PubMedCrossRefGoogle Scholar
  14. Gabbott PL, Warner TA, Jays PR, Bacon SJ (2003) Areal and synaptic interconnectivity of prelimbic (area 32), infralimbic (area 25) and insular cortices in the rat. Brain Res 993:59–71PubMedCrossRefGoogle Scholar
  15. Gabbott PL, Warner TA, Jays PR, Salway P, Busby SJ (2005) Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers. J Comp Neurol 492:145–177PubMedCrossRefGoogle Scholar
  16. Gersner R, Toth E, Isserles M, Zangen A (2010) Site-specific antidepressant effects of repeated subconvulsive electrical stimulation: potential role of brain-derived neurotrophic factor. Biol Psychiatry 67:125–132PubMedCrossRefGoogle Scholar
  17. Guze SB, Robins E (1970) Suicide and primary affective disorders. Br J Psychiatry 117:437–438PubMedCrossRefGoogle Scholar
  18. Hamani C, Nobrega JN (2010) Deep brain stimulation in clinical trials and animal models of depression. Eur J Neurosci 32:1109–1117PubMedCrossRefGoogle Scholar
  19. Hamani C, Diwan M, Macedo CE, Brandao ML, Shumake J, Gonzalez-Lima F et al (2010a) Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats. Biol Psychiatry 67:117–124PubMedCrossRefGoogle Scholar
  20. Hamani C, Diwan M, Isabella S, Lozano AM, Nobrega JN (2010b) Effects of different stimulation parameters on the antidepressant-like response of medial prefrontal cortex deep brain stimulation in rats. J Psychiatr Res 44:683–687PubMedCrossRefGoogle Scholar
  21. Hamani C, Diwan M, Raymond R, Nobrega JN, Macedo CE, Brandao ML et al (2011) Electrical brain stimulation in depression: which target(s)? Biol Psychiatry 69:e7–e8CrossRefGoogle Scholar
  22. Heidbreder CA, Groenewegen HJ (2003) The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics. Neurosci Biobehav Rev 27:555–579PubMedCrossRefGoogle Scholar
  23. Heimer L, Alheid GF, de Olmos JS, Groenewegen HJ, Haber SN, Harlan RE et al (1997) The accumbens: beyond the core-shell dichotomy. J Neuropsychiatry Clin Neurosci 9:354–381PubMedGoogle Scholar
  24. Jimenez F, Velasco F, Salin-Pascual R, Hernandez JA, Velasco M, Criales JL et al (2005) A patient with a resistant major depression disorder treated with deep brain stimulation in the inferior thalamic peduncle. Neurosurgery 57:585–593; discussion 585–593Google Scholar
  25. Jodo E, Chiang C, Aston-Jones G (1998) Potent excitatory influence of prefrontal cortex activity on noradrenergic locus coeruleus neurons. Neuroscience 83:63–79PubMedCrossRefGoogle Scholar
  26. Juckel G, Mendlin A, Jacobs BL (1999) Electrical stimulation of rat medial prefrontal cortex enhances forebrain serotonin output: implications for electroconvulsive therapy and transcranial magnetic stimulation in depression. Neuropsychopharmacology 21:391–398PubMedCrossRefGoogle Scholar
  27. Krahl SE, Senanayake SS, Pekary AE, Sattin A (2004) Vagus nerve stimulation (VNS) is effective in a rat model of antidepressant action. J Psychiatr Res 38:237–240PubMedCrossRefGoogle Scholar
  28. Li B, Suemaru K, Cui R, Araki H (2007) Repeated electroconvulsive stimuli have long-lasting effects on hippocampal BDNF and decrease immobility time in the rat forced swim test. Life Sci 80:1539–1543PubMedCrossRefGoogle Scholar
  29. Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH (2008) Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry 64:461–467PubMedCrossRefGoogle Scholar
  30. Malone DA Jr, Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN et al (2009) Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry 65:267–275PubMedCrossRefGoogle Scholar
  31. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C et al (2005) Deep brain stimulation for treatment-resistant depression. Neuron 45:651–660PubMedCrossRefGoogle Scholar
  32. Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547PubMedGoogle Scholar
  33. Ongur D, Price JL (2000) The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex 10:206–219PubMedCrossRefGoogle Scholar
  34. Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732PubMedCrossRefGoogle Scholar
  35. Porsolt RD, Anton G, Blavet N, Jalfre M (1978) Behavioural despair in rats: a new model sensitive to antidepressant treatments. Eur J Pharmacol 47:379–391PubMedCrossRefGoogle Scholar
  36. Price JL, Drevets WC (2010) Neurocircuitry of mood disorders. Neuropsychopharmacology 35:192–216PubMedCrossRefGoogle Scholar
  37. Ranck JB Jr (1975) Which elements are excited in electrical stimulation of mammalian central nervous system: a review. Brain Res 98:417–440PubMedCrossRefGoogle Scholar
  38. Sartorius A, Kiening KL, Kirsch P, von Gall CC, Haberkorn U, Unterberg AW et al (2010) Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry 67:e9–e11PubMedCrossRefGoogle Scholar
  39. Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N et al (2008) Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 33:368–377PubMedCrossRefGoogle Scholar
  40. Segal S, Tetens J, Kegeles L, Castrillon J, Steinfeld S, Krueger K et al (2007) The effects of local high frequency electrical stimulation on monoamine efflux in the subgenual cingulate cortex (Brodmann Area 25) and its striatal and thalamic projection regions. Program No 26722/W1, Society for Neuroscience, San DiegoGoogle Scholar
  41. Shimizu E, Hashimoto K, Okamura N, Koike K, Komatsu N, Kumakiri C et al (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54:70–75PubMedCrossRefGoogle Scholar
  42. Slattery DA, Neumann I, Cryan JF (2010) Transient inactivation of the infralimbic cortex induces antidepressant-like effects in the rat. J Psychopharmacol 25:1295–1303PubMedCrossRefGoogle Scholar
  43. Smith MA, Makino S, Kvetnansky R, Post RM (1995) Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci 15:1768–1777PubMedGoogle Scholar
  44. Takagishi M, Chiba T (1991) Efferent projections of the infralimbic (area 25) region of the medial prefrontal cortex in the rat: an anterograde tracer PHA-L study. Brain Res 566:26–39PubMedCrossRefGoogle Scholar
  45. Temel Y, Boothman LJ, Blokland A, Magill PJ, Steinbusch HW, Visser-Vandewalle V et al (2007) Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus. Proc Natl Acad Sci U S A 104:17087–17092PubMedCrossRefGoogle Scholar
  46. Uylings HB, Groenewegen HJ, Kolb B (2003) Do rats have a prefrontal cortex? Behav Brain Res 146:3–17PubMedCrossRefGoogle Scholar
  47. Vertes RP (1991) A PHA-L analysis of ascending projections of the dorsal raphe nucleus in the rat. J Comp Neurol 313:643–668PubMedCrossRefGoogle Scholar
  48. Vitek JL (2002) Mechanisms of deep brain stimulation: excitation or inhibition. Mov Disord 17(Suppl 3):S69–S72PubMedCrossRefGoogle Scholar
  49. Willner P (2005) Chronic mild stress (CMS) revisited: consistency and behavioural-neurobiological concordance in the effects of CMS. Neuropsychobiology 52:90–110PubMedCrossRefGoogle Scholar
  50. Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology (Berl) 93:358–364CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Brian W. Scott
    • 1
  • José N. Nobrega
    • 1
  • Clement Hamani
    • 1
    • 2
    Email author
  1. 1.Neuroimaging Research SectionCentre for Addiction and Mental HealthTorontoCanada
  2. 2.Division of NeurosurgeryToronto Western HospitalTorontoCanada

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