The medial forebrain bundle—a white matter pathway projecting from the ventral tegmental area—is a structure that has been under a lot of scrutinies recently due to its implications in the modulation of certain affective disorders such as major depression. In the following, we will discuss major depression in the context of being a disorder dependent on multiple relevant networks, the pathological performance of which is responsible for the manifestation of various symptoms of the disease which extend into emotional, motivational, physiological, and also cognitive domains of daily living. We will focus on the reward system, an evolutionarily conserved pathway whose underperformance leads to anhedonia and lack of motivation, which are key traits in depression. In the field of deep brain stimulation (DBS), different “hypothesis-driven” targets have been chosen as the subject of clinical trials on efficacy in the treatment-resistant depressed patient. The “medial forebrain bundle” is one such target for DBS, and has had remarkably rapid success in alleviating depressive symptoms, improving anhedonia and motivation. We will review what we have learned from pre-clinical animal studies on defining this white matter tract, its connectivity, and the complex molecular (i.e., neurotransmitter) mechanisms by which its modulation exerts its effects. Imaging studies in the form of tractographic depictions have elucidated its presence in the human brain. Such has led to ongoing clinical trials of DBS targeting this pathway to assess efficacy, which is promising yet still lack in sufficient numbers. Ultimately, one must confirm the mechanism of action and validate proof of antidepressant effect in order to have such treatment become mainstream, to promote widespread improvement in the quality of life of suffering patients.
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Coenen VA, Schlaepfer TE, Sajonz B, Döbrössy M, Kaller CP, Urbach H, et al. Tractographic description of major subcortical projection pathways passing the anterior limb of the internal capsule. Corticopetal Organ Netw Relevant Psychiatr Disord Neuroimage Clin. 2020;25:102165.
Schlaepfer TE, Bewernick BH, Kayser S, Mädler B, Coenen VA. Rapid effects of deep brain stimulation for treatment-resistant major depression. Biol Psychol. 2013;73:1204–12.
Fenoy AJ, Schulz PE, Selvaraj S, Burrows CL, Zunta-Soares G, Durkin K, et al. A longitudinal study on deep brain stimulation of the medial forebrain bundle for treatment-resistant depression. Transl Psychiatry. 2018;8:111.
DiLuca M, Olesen J. The cost of brain diseases: a burden or a challenge? Neuron. 2014;82:1205–8.
Sussman M, O’sullivan AK, Sha A, Olfson M, Menzin J. Economic burden of treatment-resistant depression on the U.S. health care system. J Manag Care Spec Pharm. 2019;25:823–35.
WHO. Depression: fact sheet. Geneva: World Health Organisation; 2017. http://www.who.int/mediacentre/factsheets/fs369/en/.
Rush AJ, Trivedi MH, Stewart JW, Nierenberg AA, Fava M, Kurian BT, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168:689–701.
Ruhe HG, van Rooijen G, Spijker J, Peeters FPML, Shene AH. Staging methods for treatment resistant depression. A systematic review. J Affect Disord. 2012;137:35–45.
Rush AJ. Star-D: what have we learned? Am J Psychiatry. 2007;164:201–4.
Rush AJ. Star-D: lessons learned and future implications. Depress Anxiety. 2011;28:521–4.
Williams LM. Precision psychiatry: a neural circuit taxonomy for depression and anxiety. Lancet Psychiatry. 2016;3:472–80.
Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med. 2017;23:28–38.
Akil H, Gordon J, Hen R, Javitch J, Mayberg H, Ewen B, et al. Treatment resistant depression: a multi-scale, systems biology approach. Neurosci Biobehav Rev. 2018;84:272–88.
Coenen VA, Schlaepfer TE, Maedler B, Panksepp J. Cross-species affective functions of the medial forebrain bundle-implications for the treatment of affective pain and depression in humans. Neurosci Biobehav Rev. 2011;35:1971–81.
Coenen VA, Madler B, Schlaepfer TE. Reply to: medial forebrain bundle stimulation—speed access to an old or entry into a new depression neurocircuit? Biol Psychol. 2013;74:e45–6.
Castro DC, Berridge KC. Advances in the neurobiological bases for food “liking” versus “wanting”. Physiol Behav. 2014;136:22–30. Sep.
Berridge KC, Kringelbach ML. Pleasure systems in the brain. Neuron. 2015;86:646–64.
Döbrössy MD, Furlanetti LL, Coenen VA. Electrical stimulation of the medial forebrain bundle in pre-clinical studies of psychiatric disorders. Neurosci Biobehav Rev. 2015;49:32–42.
Dean J, Keshavan M. The neurobiology of depression: an integrated view. Asian J Psychiatry. 2017;27:101–11.
Disner SG, Beever CG, Haig EA, Beck A. Neural mechanisms of the cognitive model of depression. Nat Rev Neurosci. 2011;12:467–77.
Li BJ, Friston K, Mody M, Wang HN. A brain network model for depression: from symptom understanding to disease intervention. CNS Neurosci Ther. 2018;24:1004–19.
Panksepp J, Wright JS. An evolutionary framework to understand foraging, wanting, and desire: the neuropsychology of the seeking system. Neuropsychoanalysis. 2012;14:59–75.
Alves-Pinto A, Rus OG, Reess TJ, Wohlschlager A, Wagner G, Berberich G, et al. Altered reward-related effective connectivity in obsessive-compulsive disorder: an fMRI study. J Psychiatry Neurosci. 2019;44:1–12.
Coenen VA, Schlaepfer TE, Goll P, Reinacher PC, Voderholzer U, Terbartz van Elst L, et al. The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder. CNS Spectr. 2016;493:1–8.
Keren H, O’Callaghan G, Vidal-Ribas P, Buzzell GA, Brotman MA, Leibenluft E, et al. Reward processing in depression: a conceptual and meta-analytic review across FMRI and EEG studies. Am. J. Psychiatry. 2018;175:1111–20.
Anisman H, Matheson K. Stress, depression, and anhedonia: caveats concerning animal models. Neurosci Biobehav Rev. 2005;29:525–46.
Blood AJ, Iosifescu DV, Makris N, Perlis RH, Kennedy DN, Dougherty DD, et al. Microstructural abnormalities in subcortical reward circuitry of subjects with major depressive disorder. PLoS ONE. 2010;5:e13945.
Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM. Neurobiology of depression. Neuron. 2002;34:13–25.
Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci. 2013;14:609–25.
Schlaepfer TE, Bewernick BH, Kayser S, Hurlemann R, Coenen VA. Deep brain stimulation of the human reward system for major depression–rationale, outcomes and outlook. Neuropsychopharmacology. 2014;39:1303–14.
Abler B, Greenhouse I, Ongur D, Walter H, Heckers S. Abnormal reward system activation in mania. Neuropsychopharmacology. 2008;33:2217–27.
Coenen VA, Honey CR, Hurwitz T, Rahman AA, Mcmaster J, Bürgel U, et al. Medial forebrain bundle stimulation as a pathophysiological mechanism for hypomania in subthalamic nucleus deep brain stimulation for Parkinson’s disease. Neurosurgery. 2009;64:1106–14.
Dichter GS, Kozink RV, McClernon FJ, Smoski MJ. Remitted major depression is characterized by reward network hyperactivation during reward anticipation and hypoactivation during reward outcomes. J Affect Disord. 2012;136:1126–34.
Öhman A, Carlsson K, Lundqvist D. On the unconscious subcortical origin of human fear. J Phys Behav. 2007;92:180–5.
Gross CT. The many paths to fear. Nat Rev Neurosci. 2012;13:651–8. Sep.
Motta SC, Carobrez AP, Canteras NS. The periaqueductal gray and primal emotional processing critical to influence complex defensive responses, fear learning and reward seeking. Neurosci Biobehav Rev. 2017;76:39–47. May(Pt A).
Panksepp J. Feeling the pain of social loss. Science. 2003;302:237–9.
Eisenberger NI, Lieberman MD, Williams KD. Does rejection hurt? An FMRI study of social exclusion. Science. 2003;302:290–2.
Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357–81.
Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, et al. Three-year outcomes in deep brain stimulation for highly resistant obsessive–compulsive disorder. Neuropsychopharmacology. 2006;31:2384–93.
Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, et al. Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651–60.
Hamani C, Mayberg H, Stone S, Laxton A, Haber S, Lozano AM. The subcallosal cingulate gyrus in the context of major depression. Biol Psychiatry. 2011;69:301–8.
Drevets WC, Price JL, Simpson JR Jr, Todd RD, Reich T, Vannier M, et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386:824–7.
Lozano AM, Mayberg HS, Giacobbe P, Hamani C, Craddock RC, Kennedy SH. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychiatry. 2008;64:461–7.
Holtzheimer PE, Husain MM, Lisanby SH, Taylor SF, Whitworth LA, McClintock S, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry. 2017;4:839–49.
Riva-Posse P, Choi KS, Holtzheimer PE, Crowell AL, Garlow SJ, Rajendra JK, et al. A connectomic approach for sub- callosal cingulate deep brain stimulation surgery: prospective targeting in treatment-resistant depression. Mol Psychol. 2017;62:10.
Malone DA Jr, Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, et al. Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009;65:267–75. Feb 15.
Dougherty DD, Rezai AR, Carpenter LL, Howland RH, Bhati MT, O’Reardon JP, et al. A randomized sham-controlled trial of deep brain stimulation of the ventral capsule/ventral striatum for chronic treatment-resistant depression. Biol Psychiatry. 2015;78:240–8. Aug 15.
Bergfeld IO, Mantione M, Hoogendoorn ML, Ruhé HG, Notten P, van Laarhoven J, et al. Deep brain stimulation of the ventral anterior limb of the internal capsule for treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2016;73:456–64. May 1.
Bewernick BH, Kayser S, Sturm V, Schlaepfer TE. Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. Neuropsychopharmacology. 2012;37:1975–85. Aug.
Fitzgerald PB, Segrave R, Richardson KE, Knox LA, Herring S, Daskalakis ZJ, et al. A pilot study of bed nucleus of the stria terminalis deep brain stimulation in treatment resistant depression. Brain Stimul. 2018;11:921–8. Jul-Aug.
Raymaekers S, Luyten L, Bervoets C, Gabriëls L, Nuttin B. Deep brain stimulation for treatment-resistant major depressive disorder: a comparison of two targets and long-term follow-up. Transl Psychiatry. 2017;7:e1251. Oct 31.
Lee DJ, Dallapiazza RF, De Vloo P, Elias GJB, Fomenko A, Boutet A, et al. Inferior thalamic peduncle deep brain stimulation for treatment-refractory obsessive-compulsive disorder: a phase 1 pilot trial. Brain Stimul. 2019;12:344–52. Mar-Apr.
Jiménez F, Nicolini H, Lozano AM, Piedimonte F, Salín R, Velasco F. Electrical stimulation of the inferior thalamic peduncle in the treatment of major depression and obsessive compulsive disorders. World Neurosurg. 2013;80:e17–25. Sep-OctS30.
Sartorius A, Kiening KL, Kirsch P, von Gall CC, Haberkorn U, Unterberg AW, et al. Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient. Biol Psychiatry 2010;67:e9–e11.
Döbrössy MD, Ramanathan C, Ashouri Vajari D, Tong Y, Schlaepfer T, Coenen VA. Neuromodulation in psychiatric disorders: experimental and clinical evidence for reward and motivation network deep brain stimulation: focus on the medial forebrain bundle. Eur J Neurosci. 2020; 15. https://doi.org/10.1111/ejn.14975.
Nieuwenhuys R, Geeraedts LMG, Veening JG. The medial forebrain bundle of the rat. I. General Introduction. J Comp Neurol. 1982;206:49–81.
Nieuwenhuys R. The greater limbic system, the emotional motor system and the brain. Prog Brain Res. 1996;107:551–80.
Lammel S, Lim BK, Malenka RC. Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology. 2014;76:351–9. JanPt B(0 0).
Koob GF, Le Moal M. Addiction and the brain antireward system. Annu Rev Psychol. 2008;59:29–53.
Ikemoto S, Wise RA. Rewarding effects of the cholinergic agents carbachol and neostigmine in the posterior ventral tegmental area. J Neurosci. 2002;22:9895–904.
Sharp C, Monterosso J, Montague PR. Neuroeconomics: a bridge for translational research. Biol Psychiatry. 2012;72:87–92.
Sesack SR, Grace AA. Cortico-Basal Ganglia reward network: microcircuitry. Neuropsychopharmacology. 2010;35:27–47.
Ikemoto S, Panksepp J. The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res Brain Res Rev. 1999;31:6–41.
Alcaro A, Panksepp J. The SEEKING mind: primal neuro-affective substrates for appetitive incentive states and their pathological dynamics in addictions and depression. Neurosci Biobehav Rev. 2011;35:1805–20.
Panksepp, J. Affective neuroscience: the foundations of human and animal emotions. New York: Oxford University Press; 1998.
Wise A, McDevitt RA. Drive and reinforcement circuitry in the brain: origins, neurotransmitters, and projection fields. Neuropsychopharmacol Publ Am Coll Neuropsychopharmacol. 2018;43:680–9.
Heshmati M, Russo SJ. Anhedonia and the brain reward circuitry in depression. Curr Behav Neurosci Rep. 2015;2:146–53.
Witten IB, Steinberg EE, Lee SY, Davidson TJ, Zalocusky KA, Brodsky M. et al. Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine-mediated reinforcement. Neuron. 2011;72:721–33.
Tan KR, et al. GABA neurons of the VTA drive conditioned place aversion. Neuron. 2012;73:1173–83.
Tsai HC, Zhang F, Adamantidis A, Stuber GD, Bonci A, de Leca L, et al. Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science. 2009;324:1080–4.
van Zessen R, Phillips JL, Budygin EA, Stuber GD. Activation of VTA GABA neurons disrupts reward consumption. Neuron. 2012;73:1184–94.
Tye KM, Mirzabekov JJ, Warden MR, Ferenczi EA, Tsai HC, Finkelstein J, et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature. 2013;493:537–41.
Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, et al. Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature. 2013;493:532–6.
Olds J, Milner, P. Positive reinforcement produced by electrical stimulation of the septal area and other regions of rat brain. J Comp Physiol Psychol. 1954;47:419–27.
Furlanetti LL, Coenen VA, Aranda IA, Döbrössy MD. Chronic deep brain stimulation of the medial forebrain bundle reverses depressive-like behavior in a hemiparkinsonian rodent model. Exp Brain Res. 2015;233:3073–85.
Thiele S, Furlanetti L, Pfeiffer L-M, Coenen VA, Döbrössy MD. The effects of bilateral, continuous, and chronic deep brain stimulation of the medial forebrain bundle in a rodent model of depression. Exp Neurol. 2018;303:153–61.
Edemann-Callesen H, Voget M, Empl L, Vogel M, Wieske F, Rummel J, et al. Medial forebrain bundle deep brain stimulation has symptom-specific anti-depressant effects in rats and as opposed to ventromedial prefrontal cortex stimulation interacts with the reward system. Brain Stimul. 2015;8:714–23. Jul-Aug.
Dandekar MP, Saxena A, Scaini G, Shin JH, Migut A, Giridharan VV, et al. Medial forebrain bundle deep brain stimulation reverses anhedonic-like behavior in a chronic model of depression: the importance of BDNF and inflammatory cytokines. Mol Neurobiol. 2019;56:4364–80.
Dandekar MP, Luse D, Hoffmann C, Cotton P, Peery T, Ruiz C, et al. Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle. J Affect Disord. 2017;217:80–88.
Furlanetti LL, Coenen VA, Döbrössy MD. Ventral tegmental area dopaminergic lesion-induced depressive phenotype in the rat is reversed by deep brain stimulation of the medial forebrain bundle. Behav Brain Res. 2016;299:132–40.
Thiele S, Sörensen A, Weis J, Braun F, Meyer PT, Coenen VA, et al. Deep brain stimulation of the medial forebrain bundle in a rodent model of depression: exploring dopaminergic mechanisms with raclopride and Micro-PET. Stereotact. Funct Neurosurg. 2020;98:1–13.
Corbett D, Wise RA. Intracranial self-stimulation in relation to the ascending dopaminergic systems of the midbrain: a moveable electrode mapping study. Brain Res. 1980;185:1–15. Mar 3.
Fibiger HC, LePiane FG, Jakubovic A, Phillips AG. The role of dopamine in intracranial self-stimulation of the ventral tegmental area. J Neurosci. 1987;7:3888–96. Dec.
German DC, Bowden DM. Catecholamine systems as the neural substrate for intracranial self-stimulation: a hypothesis. Brain Res. 1974;73:381–419. Jun 28.
Nakahara D, Ozaki N, Miura Y, Miura H, Nagatsu T. Increased dopamine and serotonin metabolism in rat nucleus accumbens produced by intracranial self-stimulation of medial forebrain bundle as measured by in vivo microdialysis. Brain Res. 1989;495:178–81. Aug 21.
Bregman T, Reznikov R, Diwan M, Raymond R, Butson CR, Nobrega JN, et al. Antidepressant-like effects of medial forebrain bundle deep brain stimulation in rats are not associated with accumbens dopamine release. Brain Stimul. 2015;8:708–13.
Ou Y, Buchanan AM, Witt CE, Hashemi P. Frontiers in electrochemical sensors for neurotransmitter detection: towards measuring neurotransmitters as chemical diagnostics for brain disorders. Anal Methods. 2019;11:2738–55.
Ranck JB Jr. Which elements are excited in electrical stimulation of mammalian central nervous system: a review. Brain Res. 1975;98:417–40.
Kringelbach ML, Jenkinson N, Owen SLF, Aziz TZ. Translational principles of deep brain stimulation. Nat Rev Neurosci. 2007;8:623–35.
Phillips PEM, Robinson DL, Stuber GD, Carelli RM, Wightman RM. Real-time measurements of phasic changes in extracellular dopamine concentration in freely moving rats by fast-scan cyclic voltammetry. Methods Mol Med. 2003;79:443–64.
Lohani S, Martig AK, Deisseroth K, Witten IB, Moghaddam B. Dopamine modulation of prefrontal cortex activity is manifold and operates at multiple temporal and spatial scales. Cell Rep. 2019;27:99–114. e6.
Ungless MA, Magill PJ, Bolam JP. Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli. Science. 2004;303:2040–2.
Valenti O, Gill KM, Grace AA. Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: response alteration by stress pre-exposure. Eur J Neurosci. 2012;35:1312–21.
Bunney BS, Walters JR, Roth RH, Aghajanian GK. Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity. J Pharmacol Exp Ther. 1973;185:560–71.
Grace AA, Bunney BS. Intracellular and extracellular electrophysiology of nigral dopaminergic neurons-1. Identif Charact Neurosci. 1983;10:301–15.
Ewing AG, Bigelow JC, Wightman RM. Direct in vivo monitoring of dopamine released from two striatal compartments in the rat. Science. 1983;221:169–71.
Kuhr WG, Wightman RM, Rebec GV. Dopaminergic neurons: simultaneous measurements of dopamine release and single-unit activity during stimulation of the medial forebrain bundle. Brain Res. 1987;418:122–8.
Kuhr WG, Ewing AG, Caudill WL, Wightman RM. Monitoring the stimulated release of dopamine with in vivo voltammetry. I: characterization of the response observed in the caudate nucleus of the rat. J Neurochem. 1984;43:560–9.
Stamford JA, Kruk ZL, Millar J. Measurement of stimulated dopamine release in the rat by in vivo voltammetry: the influence of stimulus duration on drug responses. Neurosci Lett. 1986;69:70–73.
Stamford JA, Kruk ZL, Millar J. Accommodation of rat nigrostriatal dopamine neurones to high frequency electrical stimulation of the median forebrain bundle: in vivo voltammetric data. Neurosci Lett. 1987;82:172–6.
Gratton A, Hoffer BJ, Gerhardt GA. Effects of electrical stimulation of brain reward sites on release of dopamine in rat: an in vivo electrochemical study. Brain Res Bull. 1988;21:319–24.
Gonon FG. Nonlinear relationship between impulse flow and dopamine released by rat midbrain dopaminergic neurons as studied by in vivo electrochemistry. Neuroscience. 1988;24:19–28.
Klanker M, Feenstra M, Willuhn I, Denys D. Deep brain stimulation of the medial forebrain bundle elevates striatal dopamine concentration without affecting spontaneous or reward-induced phasic release. Neuroscience. 2017;364:82–92.
Howe MW, Tierney PL, Sandberg SG, Phillips PEM, Graybiel AM. Prolonged dopamine signalling in striatum signals proximity and value of distant rewards. Nature. 2013;500:575–9.
Cohen JY, Haesler S, Vong L, Lowell BB, Uchida N. Neuron-type-specific signals for reward and punishment in the ventral tegmental area. Nature. 2012;482:85–8. Jan 18.
Matsumoto M, Hikosaka O. Two types of dopamine neuron distinctly convey positive and negative motivational signals. Nature. 2009;459:837–41. Jun 11.
Schultz W, Dayan P, Montague PR. A neural substrate of prediction and reward. Science. 1997;275:1593–9. Mar 14.
Waelti P, Dickinson A, Schultz W. Dopamine responses comply with basic assumptions of formal learning theory. Nature. 2001;412:43–8. Jul 5.
Bayer HM, Glimcher PW. Midbrain dopamine neurons encode a quantitative reward prediction error signal. Neuron. 2005;47:129–41. Jul 7.
Settell ML, Testini P, Cho S, Lee JH, Blaha CD, Jo HJ, et al. Functional circuitry effect of ventral tegmental area deep brain stimulation: imaging and neurochemical evidence of mesocortical and mesolimbic pathway modulation. Front Neurosci. 2017;11:104.
Ashouri Vajari D, Ramanathan C, Tong Y, Stieglitz T, Coenen VA, Döbrössy MD. Medial forebrain bundle DBS differentially modulates dopamine release in the nucleus accumbens in a rodent model of depression. Exp Neurol. 2020;327:113224.
Hamid AA, Pettibone JR, Mabrouk OS, Hetrick VL, Schmidt R, Vander Weele CM, et al. Mesolimbic dopamine signals the value of work. Nat Neurosci. 2016;19:117–26.
Ikemoto S. Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory. Neurosci Biobehav Rev. 2010;35:129–50.
Ikemoto S. Dopamine reward circuitry: two projection systems from the ventral midbrain to the nucleus accumbens–olfactory tubercle complex. Brain Res Rev. 2007;56:27–78.
Gradinaru V, Mogri M, Thompson KR, Henderson JM, Deisseroth K. Optical deconstruction of parkinsonian neural circuitry. Science. 2009;324:354–9. PMID:19299587.
Taber MT, Das S, Fibiger HC. Cortical regulation of subcortical dopamine release: mediation via the ventral tegmental area. J Neurochem. 1995;65:1407–10. PMID: 7643120.
Karreman M, Westerink BH, Moghaddam B. Excitatory amino acid receptors in the ventral tegmental area regulate dopamine release in the ventral striatum. J Neurochem. 1996;67:601–7.
Helbing C, Brocka M, Scherf T, Lippert MT, Angenstein F. The role of the mesolimbic dopamine system in the formation of blood-oxygen-level dependent responses in the medial prefrontal/anterior cingulate cortex during high-frequency stimulation of the rat perforant pathway. J Cereb Blood Flow Metab. 2016;36:2177–93. Dec.
Schoene-Bake JC, Parpaley Y, Weber B, Panksepp J, Hurwitz TA, Coenen VA. Tractographic analysis of historical lesion surgery for depression. Neuropsychopharmacology. 2010;35:2553–63.
Coenen VA, Panksepp J, Hurwitz TA, Urbach H, Madler B. Human medial forebrain bundle (MFB) and anterior thalamic radiation (ATR): imaging of two major subcortical pathways and the dynamic balance of opposite affects in understanding depression. J Neuropsychiatry Clin Neurosci. 2012;24:223–36.
Coenen VA, Schumacher LV, Kaller C, Schlaepfer TE, Reinacher PC, Egger K, et al. The anatomy of the human medial forebrain bundle: ventral tegmental area connections to reward-associated subcortical and frontal lobe regions. NeuroImage Clin. 2018c;18:770–83.
Frankle WG, Laruelle M, Haber SN. Prefrontal cortical projections to the midbrain in primates: evidence for a sparse connection. Neuropsychopharmacology. 2006;31:1627–36.
Greenberg BD, Rauch SL, Haber SN. Invasive circuitry-based neurotherapeutics: stereotactic ablation and deep brain stimulation for OCD. Neuropsychopharmacology. 2010;35:317–36.
Haynes WIA, Haber SN. The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for Basal Ganglia models and deep brain stimulation. J Neurosci. 2013;33:4804–14.
Nanda P, Banks GP, Pathak YJ, Sheth SA. Connectivity-based parcellation of the anterior limb of the internal capsule. Hum Brain Mapp. 2017;38:6107–17.
Safadi Z, Grisot G, Jbabdi S, Behrens TE, Heilbronner SR, McLaughlin NCR, et al. Functional segmentation of the anterior limb of the internal capsule: linking white matter abnormalities to specific connections. J Neurosci. 2018a;38:2106–17.
Safadi Z, Grisot G, Jbabdi S, Behrens TE, Heilbronner SR, McLaughlin NCR, et al. Functional segmentation of the anterior limb of the internal capsule: linking white matter abnormalities to specific connections. J Neurosci. 2018b;38:2106–17.
Lehman JF, Greenberg BD, McIntyre CC, Rasmussen SA, Haber SN. Rules ventral prefrontal cortical axons use to reach their targets: implications for diffusion tensor imaging tractography and deep brain stimulation for psychiatric illness. J Neurosci. 2011;31:10392–402.
Makris N, Rathi Y, Mouradian P, Bonmassar G, Papadimitriou G, Ing WI, et al. Variability and anatomical specificity of the orbitofrontothalamic fibers of passage in the ventral capsule/ventral striatum (VC/VS): precision care for patient-specific tractography-guided targeting of deep brain stimulation (DBS) in obsessive compulsive disorder (OCD). Brain Imaging Behav. 2016;10:1054–67.
Baldermann JC, Melzer C, Zapf A, Kohl S, Timmermann L, Tittgemeyer M, et al. Connectivity profile predictive of effective deep brain stimulation in obsessive compulsive disorder. Biol Psychiatry 2019;85:735–43.
Panksepp J. The basic emotional circuits of mammalian brains: do animals have affective lives? Neurosci Biobehav Rev. 2011;35:1791–804.
Nieuwenhuys R, Voogd J, van Huijzen C. The human central nervous system. A Synopsis and Atlas, Fourth Edition. Heidelberg: Springer; 2008.
Panksepp J. Affective consciousness: core emotional feelings in animals and humans. Conscious Cogn. 2005;14:30–80.
Neubert F-X, Mars RB, Sallet J, Rushworth MFS. Connectivity reveals relationship of brain areas for reward-guided learning and decision making in human and monkey frontal cortex. Proc Natl Acad Sci USA 2015;112:E2695–E2704.
Haber SN, Yendiki A, Jbabdi S. Four deep brain stimulation targets for obsessive-compulsive disorder: Are they different? Biol Psychiatry. 2020;S0006-3223:31773-X. https://doi.org/10.1016/j.biopsych.2020.06.031. Online ahead of print.
Schmahmann J, Pandya D. Fiber pathways of the brain. 1st edition. New York: Oxford University Press;2006.
Gaspar P, Neurology ISOC. Topography and collateralization of the dopaminergic projections to motor and lateral prefrontal cortex in owl monkeys. Wiley Online Library;1992.
Petersen MV, Mlakar J, Haber SN, Parent M, Smith Y, Strick PL, et al. Holographic reconstruction of axonal pathways in the human brain. Neuron. 2019; 1–16.
Hurwitz TA, Mandat T, Forster B, Honey C. Tract identification by novel MRI signal changes following stereotactic anterior capsulotomy. Stereotact Funct Neurosurg. 2006b;84:228–35.
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry. 1979;134:382–9.
Bewernick BH, Kayser S, Gippert SM, Switala C, Coenen VA, Schlaepfer TE. Deep brain stimulation to the medial forebrain bundle for depression-long-term outcomes and a novel data analysis strategy. Brain Stimul. 2017;10:664–71.
Coenen VA, Bewernick BH, Kayser S, Kilian H, Boström J, Greschus S, et al. Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial. Neuropsychopharmacology. 2019a;26:587.
Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;6:278–96.
Jones SH, Thornicroft G, Coffey M, Dunn G. A brief mental health outcome scale-reliability and validity of the Global Assessment of Functioning (GAF). Br J Psychiatry. 1995;166:654–9.
First MB, Spitzer RL, Gibbon M, Williams JBW, Benjamin LS. Structured clinical interview for DSM-IV Axis II personality disorders (SCID II). Washington, DC: American Psychiatric Press;1996.
Millon T, Millon C, Davis R. Millon clinical multiaxial inventory-III (MCMI-III) manual. Minneapolis, MN: National Computer Systems;1994.
Fenoy AJ, Schulz P, Selvaraj S, Burrows C, Spiker D, Cao B, et al. Deep brain stimulation of the medial forebrain bundle: distinctive responses in resistant depression. J Affect Disord. 2016;203:143–51. Oct 3. PMID: 27288959.
Perez-Caballero L, Perez-Egea R, Romero-Grimaldi C, Puigdemont D, Molet J, Caso JR, et al. Early responses to deep brain stimulation in depression are modulated by anti-inflammatory drugs. Mol Psychiatry. 2014;19:607–14.
Chang SY, Shon YM, Agnesi F, Lee KH. Microthalamotomy effect during deep brain stimulation: potential involvement of adenosine and glutamate efflux. Conf Proc IEEE Eng Med Biol Soc. 2009, 3294–7.
Fenoy AJ, Goetz L, Chabardès S, Xia Y. Deep brain stimulation: are astrocytes a key driver behind the scene? CNS Neurosci Ther 2014;20:191–201.
Naudet F, Millet B, Reymann JM, Falissard B. Improving study design for anti- depressant effectiveness assessment. Int J Methods Psychiatr Res. 2013;22:217–31.
Schatzberg AF, Kraemer HC. Use of placebo control groups in evaluating efficacy of treatment of unipolar major depression. Biol Psychiatry. 2000;47:736–44.
Kilian HM, Meyer DM, Bewernick BH, Spanier S, Coenen VA, Schlaepfer TE. Discontinuation of superolateral medial forebrain bundle deep brain stimulation for treatment-resistant depression leads to critical relapse. Biol Psychiatry. 2018;S0006-3223:31748–7. Sep 22. pii.
Martín-Blanco A, Serra-Blasco M, Pérez-Egea R, de Diego-Adeliño J, Carceller-Sindreu M, Puigdemont D, et al. Immediate cerebral metabolic changes induced by discontinuation of deep brain stimulation of subcallosal cingulate gyrus in treatment-resistant depression. J Affect Disord. 2015;173:159–62.
Evers J, Lowery M. The active electrode in the living brain: the response of the brain parenchyma to chronically implanted deep brain stimulation electrodes. Oper Neurosurg. 2020 Oct 19:opaa326. https://doi.org/10.1093/ons/opaa326.
Vedam-Mai V, Rodgers C, Gureck A, Vincent M, Ippolito G, Elkouzi A, et al. Deep brain stimulation associated gliosis: a post-mortem study. Parkinsonism Relat Disord. 2018;54:51–55. Sep.
Ruge D, Cif L, Limousin P, Gonzalez V, Vasques X, Hariz MI, et al. Shaping reversibility? Long-term deep brain stimulation in dystonia: the relationship between effects on electrophysiology and clinical symptoms. Brain. 2011;134:2106–15.
Ruge D, Tisch S, Hariz MI, Zrinzo L, Bhatia KP, Quinn NP, et al. Deep brain stimulation effects in dystonia: time course of electrophysiological changes in early treatment. Mov Disord. 2011;26:1913–21.
Sani S, Busnello J, Kochanski R, Cohen Y, Gibbons RD. High-frequency measurement of depressive severity in a patient treated for severe treatment-resistant depression with deep-brain stimulation. Transl Psychiatry. 2017;7:e1207. Aug 15.
Kelley ME, Franco AR, Mayberg HS, Holtzheimer PE. The illness density index (IDI): a longitudinal measure of treatment efficacy. Clin Trials. 2012;9:596e604.
Puigdemont D, Portella M, Perez-Egea R, Molet J, Gironell A, de Diego- Adelino J, et al. A randomized double-blind crossover trial of deep brain stimulation of the subcallosal cingulate gyrus in patients with treatment-resistant depression: a pilot study of relapse prevention. J psychiatry Neurosci JPN. 2015;40:130295.
Lozano AM, Giacobbe P, Hamani C, Rizvi SJ, Kennedy SH, Kolivakis TT, et al. A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. J Neurosurg. 2012;116:315–22.
Blomstedt P, Naesström M, Bodlund O. Deep brain stimulation in the bed nucleus of the stria terminalis and medial forebrain bundle in a patient with major depressive disorder and anorexia nervosa. Clin Case Rep. 2017;5:679–84.
Davidson B, Giacobbe P, Mithani K, Levitt A, Rabin JS, Lipsman N, et al. Lack of clinical response to deep brain stimulation of the medial forebrain bundle in depression. Brain Stimul. 2020;13:1268–70.
Fenoy A. Challenges in deep brain stimulation for depression. Braz J Psychiatry. 2020;42:347–8. Aug.
The Center of Excellence on Mood Disorders is funded by the Pat Rutherford Jr. Chair in Psychiatry, John S. Dunn Foundation, and Anne and Don Fizer Foundation Endowment for Depression Research.
Conflict of interest
JQ reported no biomedical financial interests or potential conflicts of interest. AJF serves as a consultant for Medtronic, Inc. JCS receives grant/research support from Bristol-Meyers Squibb, Forest Laboratories, Merck and Elan Pharmaceuticals, and serves as a consultant for Pfizer, Abbot, and Astellas Pharma, Inc.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Fenoy, A.J., Quevedo, J. & Soares, J.C. Deep brain stimulation of the “medial forebrain bundle”: a strategy to modulate the reward system and manage treatment-resistant depression. Mol Psychiatry (2021). https://doi.org/10.1038/s41380-021-01100-6