Login to MyKarger

New to MyKarger? Click here to sign up.

Login with Facebook

Forgot Password? Reset your password

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login (Shibboleth)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Table of Contents
Vol. 87, No. 4, 2009
Issue release date: August 2009
Section title: New Directions
Free Access
Stereotact Funct Neurosurg 2009;87:256–265

The Hippocampus and Nucleus Accumbens as Potential Therapeutic Targets for Neurosurgical Intervention in Schizophrenia

Mikell C.B. · McKhann G.M. · Segal S. · McGovern R.A. · Wallenstein M.B. · Moore H.
Department of Neurological Surgery, Columbia University, New York, N.Y., USA
email Corresponding Author

Holly Moore, PhD

Columbia University, Department of Psychiatry

1051 Riverside Dr., Mail Unit 14

New York, NY 10032 (USA)

Tel. +1 212 543 6938, Fax +1 212 543 1017, E-Mail hm2035@columbia.edu


  1. Tandon R, Keshavan MS, Nasrallah HA: Schizophrenia, ‘just the facts’ what we know in 2008. 2. Epidemiology and etiology. Schizophr Res 2008;102:1–18.
  2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Text Revision. Washington, American Psychiatric Association, 1994, p 298.
  3. Carlsson A, Lindqvist M: Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh) 1963;20:140–144.
  4. Laruelle M, Frankle WG, Narendran R, Kegeles LS, Abi-Dargham A: Mechanism of action of antipsychotic drugs: from dopamine D(2) receptor antagonism to glutamate NMDA facilitation. Clin Ther 2005;27(suppl A):S16–S24.
  5. Gray JA, Roth BL: The pipeline and future of drug development in schizophrenia. Mol Psychiatry 2007;12:904–922.
  6. Tandon R, Carpenter WT, Davis JM: First- and second-generation antipsychotics: learning from CUtLASS and CATIE. Arch Gen Psychiatry 2007;64:977–978.
  7. Kapur S, Remington G: Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia. Annu Rev Med 2001;52:503–517.
  8. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB: Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996;93:9235–9240.
  9. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M: Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998;155:761–767.
  10. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M: Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci USA 2000;97:8104–8109.
  11. Frankle WG, Gil R, Hackett E, Mawlawi O, Zea-Ponce Y, Zhu Z, Kochan LD, Cangiano C, Slifstein M, Gorman JM, Laruelle M, Abi-Dargham A: Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications. Psychopharmacology (Berl) 2004;175:473–480.
  12. Kegeles LS, Slifstein M, Frankle WG, Xu X, Hackett E, Bae SA, Gonzales R, Kim JH, Alvarez B, Gil R, Laruelle M, Abi-Dargham A: Dose-occupancy study of striatal and extrastriatal dopamine D2 receptors by aripiprazole in schizophrenia with PET and [18F]fallypride. Neuropsychopharmacology 2008;33:3111–3125.
  13. Kapur S: Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 2003;160:13–23.
  14. Grace AA, Bunney BS, Moore H, Todd CL: Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs. Trends Neurosci 1997;20:31–37.
  15. Moore H, Todd CL, Grace AA: Striatal extracellular dopamine levels in rats with haloperidol-induced depolarization block of substantia nigra dopamine neurons. J Neurosci 1998;18:5068–5077.
  16. Chrapusta SJ, Egan MF: Poor evidence for depolarization block but uncoupling of nigral from striatal dopamine metabolism after chronic haloperidol treatment in the rat. J Neural Transm 2006;113:573–582.
  17. Gründer G, Vernaleken I, Müller MJ, Davids E, Heydari N, Buchholz HG, Bartenstein P, Munk OL, Stoeter P, Wong DF, Gjedde A, Cumming P: Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo. Neuropsychopharmacology 2003;28:787–794.
  18. Samaha AN, Seeman P, Stewart J, Rajabi H, Kapur S: ‘Breakthrough’ dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci 2007;27:2979–2986.
  19. Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA, CATIE Investigators, Neurocognitive Working Group: Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch Gen Psychiatry 2007;64:633–647.
  20. Sheitman BB, Lieberman JA: The natural history and pathophysiology of treatment resistant schizophrenia. J Psychiatr Res 1998;32:143–150.
  21. Conley RR, Kelly DL: Management of treatment resistance in schizophrenia. Biol Psychiatry 2001;50:898–911.
  22. Palmer BA, Pankratz VS, Bostwick JM: The lifetime risk of suicide in schizophrenia: a reexamination. Arch Gen Psychiatry 2005;62:247–253.
  23. Neuner T, Schmid R, Wolfersdorf M, Spiessl H: Predicting inpatient suicides and suicide attempts by using clinical routine data? Gen Hosp Psychiatry 2008;30:324–330.
  24. Citrome L: The effectiveness criterion: balancing efficacy against the risks of weight gain. J Clin Psychiatry 2007;68(suppl 12):12–17.
    External Resources
  25. Mizrahi R, Rusjan P, Agid O, Graff A, Mamo DC, Zipursky RB, Kapur S: Adverse subjective experience with antipsychotics and its relationship to striatal and extrastriatal D2 receptors: a PET study in schizophrenia. Am J Psychiatry 2007;164:630–637.
  26. Monroe RR, Heath RG: Studies in Schizophrenia: A Multidisciplinary Approach to Mind-Brain Relationships. Cambridge, Harvard University Press, 1955, pp 345–389.
  27. Ressler KJ, Mayberg HS: Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic. Nat Neurosci 2007;10:1116–1124.
  28. Nuttin B, Cosyns P, Demeulemeester H, Gybels J, Meyerson B: Electrical stimulation in anterior limbs of internal capsules in patients with obsessive-compulsive disorder. Lancet 1999;354:1526.
  29. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH: Deep brain stimulation for treatment-resistant depression. Neuron 2005;45:651–660.
  30. Rauch SL, Dougherty DD, Malone D, Rezai A, Friehs G, Fischman AJ, Alpert NM, Haber SN, Stypulkowski PH, Rise MT, Rasmussen SA, Greenberg BD: A functional neuroimaging investigation of deep brain stimulation in patients with obsessive-compulsive disorder. J Neurosurg 2006;104:558–565.
  31. Greenberg BD, Malone DA, Friehs GM, Rezai AR, Kubu CS, Malloy PF, Salloway SP, Okun MS, Goodman WK, Rasmussen SA: Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder. Neuropsychopharmacology 2006;31:2384–2393.
  32. Maciunas RJ, Maddux BN, Riley DE, Whitney CM, Schoenberg MR, Ogrocki PJ, Albert JM, Gould DJ: Prospective randomized double-blind trial of bilateral thalamic deep brain stimulation in adults with Tourette syndrome. J Neurosurg 2007;107:1004–1014.
  33. Welter ML, Mallet L, Houeto JL, Karachi C, Czernecki V, Cornu P, Navarro S, Pidoux B, Dormont D, Bardinet E, Yelnik J, Damier P, Agid Y: Internal pallidal and thalamic stimulation in patients with Tourette syndrome. Arch Neurol 2008;65:952–957.
  34. El-Hai J: The Lobotomist: A Maverick Medical Genius and His Tragic Quest to Rid the World of Mental Illness. Hoboken, Wiley, 2005.
  35. Kegeles L, Frankle W, Gil R, Narendran R, Slifstein M, Hwang D-R, Cangiano C, Haber S, Abi-Dargham A, Laruelle M: Schizophrenia is associated with increased synaptic dopamine in associative rather than limbic regions of the striatum: implications for mechanisms of action of antipsychotic drugs. J Nucl Med 2006;47(suppl 1):139P.
  36. Schultz W: Multiple dopamine functions at different time courses. Annu Rev Neurosci 2007;30:259–288.
  37. Salamone JD, Correa M, Mingote SM, Weber SM: Beyond the reward hypothesis: alternative functions of NAc dopamine. Curr Opin Pharmacol 2005;5:34–41.
  38. Hollerman JR, Schultz W: Dopamine neurons report an error in the temporal prediction of reward during learning. Nat Neurosci 1998;1:304–309.
  39. Goto Y, Otani S, Grace AA: The Yin and Yang of dopamine release: a new perspective. Neuropharmacology 2007;53:583–587.
  40. Grace AA, Floresco SB, Goto Y, Lodge DJ: Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 2007;30:220–227.
  41. Goto Y, Grace AA: The dopamine system and the pathophysiology of schizophrenia: a basic science perspective. Int Rev Neurobiol 2007;78C:41–68.
  42. Legault M, Wise RA: Novelty-evoked elevations of nucleus accumbens dopamine: dependence on impulse flow from the ventral subiculum and glutamatergic neurotransmission in the ventral tegmental area. Eur J Neurosci 2001;13:819–828.
  43. Lisman JE, Grace AA: The hippocampal-VTA loop: controlling the entry of information into long-term memory. Neuron 2005;46:703–713.
  44. Grace AA, Floresco SB, Goto Y, Lodge DJ: Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 2007;30:220–227.
  45. Lawrie SM, Abukmeil SS: Brain abnormality in schizophrenia: a systematic and quantitative review of volumetric magnetic resonance imaging studies. Br J Psychiatry 1998;172:110–120.
  46. Nelson MD, Saykin AJ, Flashman LA, Riordan HJ: Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Arch Gen Psychiatry 1998;55:433–440.
  47. Velakoulis D, Wood SJ, Wong MT, McGorry PD, Yung A, Phillips L, Smith D, Brewer W, Proffitt T, Desmond P, Pantelis C: Hippocampal and amygdala volumes according to psychosis stage and diagnosis: a magnetic resonance imaging study of chronic schizophrenia, first-episode psychosis, and ultra-high-risk individuals. Arch Gen Psychiatry 2006;63:139–149.
  48. Gothelf D, Soreni N, Nachman RP, Tyano S, Hiss Y, Reiner O, Weizman A: Evidence for the involvement of the hippocampus in the pathophysiology of schizophrenia. Eur Neuropsychopharmacol 2000;10:389–395.
  49. Achim AM, Bertrand MC, Sutton H, Montoya A, Czechowska Y, Malla AK, Joober R, Pruessner JC, Lepage M: Selective abnormal modulation of hippocampal activity during memory formation in first-episode psychosis. Arch Gen Psychiatry 2007;64:999–1014.
  50. Lahti AC, Weiler MA, Holcomb HH, Tamminga CA, Carpenter WT, McMahon R: Correlations between rCBF and symptoms in two independent cohorts of drug-free patients with schizophrenia. Neuropsychopharmacology 2006;31:221–230.
  51. Duncan JS: Imaging and epilepsy. Brain 1997;120:339–377.
  52. Knowlton RC, Laxer KD, Klein G, Sawrie S, Ende G, Hawkins RA, Aassar OS, Soohoo K, Wong S, Barbaro N: In vivo hippocampal glucose metabolism in mesial temporal lobe epilepsy. Neurology 2001;57:1184–1190.
  53. Schobel SA, Lewandowski NM, Corcoran C, Pereira AC, Moore H, Tang M, Kimhy D, Brown T, Malaspina D, Small SA: The CA1 subfield is a dominant site of hippocampal hyperfunction in schizophrenia. Arch General Psychiatry, in press.
  54. Moore H, Jentsch JD, Ghajarnia M, Geyer MA, Grace AA: A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol Psychiatry 2006;60:253–264.
  55. Lodge DJ, Grace AA: Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia. J Neurosci 2007;27:11424–11430.
  56. Velasco M, Velasco F, Velasco AL: Centromedian-thalamic and hippocampal electrical stimulation for the control of intractable epileptic seizures. J Clin Neurophysiol 2001;18:495–513.
  57. Vonck K, Boon P, Achten E, De Reuck J, Caemaert J: Long-term amygdalohippocampal stimulation for refractory temporal lobe epilepsy. Ann Neurol 2002;52:556–565.
  58. Boon P, Vonck K, De Herdt V, Van Dycke A, Goethals M, Goossens L, Van Zandijcke M, De Smedt T, Dewaele I, Achten R, Wadman W, Dewaele F, Caemaert J, Van Roost D: Deep brain stimulation in patients with refractory temporal lobe epilepsy. Epilepsia 2007;48:1551–1560.
  59. Velasco AL, Velasco F, Velasco M, Trejo D, Castro G, Carrillo-Ruiz JD: Electrical stimulation of the hippocampal epileptic foci for seizure control: a double-blind, long-term follow-up study. Epilepsia 2007;48:1895–1903.
  60. Lian J, Bikson M, Sciortino C, Stacey WC, Durand DM: Local suppression of epileptiform activity by electrical stimulation in rat hippocampus in vitro. J Physiol 2003;547:427–434.
  61. Durand DM, Jensen A, Bikson M: Suppression of neural activity with high frequency stimulation. Conf Proc IEEE Eng Med Biol Soc 2006;1:1624–1625.
  62. Jensen AL, Durand DM: Suppression of axonal conduction by sinusoidal stimulation in rat hippocampus in vitro. J Neural Eng 2007;4:1–16.
  63. Wyckhuys T, De Smedt T, Claeys P, Raedt R, Waterschoot L, Vonck K, Van den Broecke C, Mabilde C, Leybaert L, Wadman W, Boon P: High frequency deep brain stimulation in the hippocampus modifies seizure characteristics in kindled rats. Epilepsia 2007;48:1543–1550.
  64. Joel D, Weiner I: The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum. Neuroscience 2000;96:451–474.
  65. Haber SN, Fudge JL, McFarland NR: Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum. J Neurosci 2000;20:2369–2382.
  66. 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.
  67. Perlstein WM, Carter CS, Noll DC, Cohen JD: Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. Am J Psychiatry 2001;158:1105–1113.
  68. Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, Moore H, Kandel ER: Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 2006;49:603–615.
  69. Greenberg BD, Gabriels LA, Malone DA Jr, Rezai AR, Friehs GM, Okun MS, Shapira NA, Foote KD, Cosyns PR, Kubu CS, Malloy PF, Salloway SP, Giftakis JE, Rise MT, Machado AG, Baker KB, Stypulkowski PH, Goodman WK, Rasmussen SA, Nuttin BJ: Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol Psychiatry 2008, E-pub ahead of print.
  70. Kuhn J, Lenartz D, Mai JK, Huff W, Lee SH, Koulousakis A, Klosterkoetter J, Sturm V: Deep brain stimulation of the nucleus accumbens and the internal capsule in therapeutically refractory Tourette-syndrome. J Neurol 2007;254:963–965.
  71. Schlaepfer TE, Cohen MX, Frick C, Kosel M, Brodesser D, Axmacher N, Joe AY, Kreft M, Lenartz D, Sturm V: Deep brain stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology 2008;33:368–377.
  72. Malone DA Jr, Dougherty DD, Rezai AR, Carpenter LL, Friehs GM, Eskandar EN, Rauch SL, Rasmussen SA, Machado AG, Kubu CS, Tyrka AR, Price LH, Stypulkowski PH, Giftakis JE, Rise MT, Malloy PF, Salloway SP, Greenberg BD: Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry 2009;65:267–275.
  73. Vassoler FM, Schmidt HD, Gerard ME, Famous KR, Ciraulo DA, Kornetsky C, Knapp CM, Pierce RC: Deep brain stimulation of the nucleus accumbens shell attenuates cocaine priming-induced reinstatement of drug seeking in rats. J Neurosci 2008;28:8735–8739.
  74. Liu HY, Jin J, Tang JS, Sun WX, Jia H, Yang XP, Cui JM, Wang CG: Chronic deep brain stimulation in the rat nucleus accumbens and its effect on morphine reinforcement. Addict Biol 2008;13:40–46.
  75. Benabid AL, Pollak P, Gervason C, Hoffmann D, Gao DM, Hommel M, Perret JE, de Rougemont J: Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337:403–406.
  76. Hamamura T, Harada T: Unique pharmacological profile of aripiprazole as the phasic component buster. Psychopharmacology (Berl) 2007;191:741–743.
  77. Grace AA: Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 1991;41:1–24.
  78. Breitenstein C, Korsukewitz C, Flöel A, Kretzschmar T, Diederich K, Knecht S: Tonic dopaminergic stimulation impairs associative learning in healthy subjects. Neuropsychopharmacology 2006;31:2552–2564.
  79. Floresco SB, Todd CL, Grace AA: Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons. J Neurosci 2001;21:4915–4922.
  80. Plewnia C, Schober F, Rilk A, Buchkremer G, Reimold M, Wächter T, Breit S, Weiss D, Krüger R, Freudenstein D: Sustained improvement of obsessive-compulsive disorder by deep brain stimulation in a woman with residual schizophrenia. Int J Neuropsychopharmacol 2008;11:1181–1183.
  81. Haber SN, Kunishio K, Mizobuchi M, Lynd-Balta E: The orbital and medial prefrontal circuit through the primate basal ganglia. J Neurosci 1995;15:4851–4867.
  82. D’Ardenne K, McClure SM, Nystrom LE, Cohen JD: BOLD responses reflecting dopaminergic signals in the human ventral tegmental area. Science 2008;319:1264–1267.
  83. Stefani A, Lozano AM, Peppe A, Stanzione P, Galati S, Tropepi D, Pierantozzi M, Brusa L, Scarnati E, Mazzone P: Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson’s disease. Brain 2007;130:1596–1607.
  84. Martin JH: Neuroanatomy: Text and Atlas. New York, McGraw-Hill Medical, 2003