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Discovering imaging endophenotypes for major depression

Abstract

Psychiatry research lacks an in-depth understanding of mood disorders phenotypes, leading to limited success of genetics studies of major depressive disorder (MDD). The dramatic progress in safe and affordable magnetic resonance-based imaging methods has the potential to identify subtle abnormalities of neural structures, connectivity and function in mood disordered subjects. This review paper presents strategies to improve the phenotypic definition of MDD by proposing imaging endophenotypes derived from magnetic resonance spectroscopy measures, such as cortical gamma-amino butyric acid (GABA) and glutamate/glutamine concentrations, and from measures of resting-state activity and functional connectivity. The proposed endophenotypes are discussed regarding specificity, mood state-independence, heritability, familiarity, clinical relevance and possible associations with candidate genes. By improving phenotypic definitions, the discovery of new imaging endophenotypes will increase the power of candidate gene and genome-wide associations studies. It will also help to develop and evaluate novel therapeutic treatments and enable clinicians to apply individually tailored therapeutic approaches. Finally, improvements of the phenotypic definition of MDD based on neuroimaging measures will contribute to a new classification system of mood disorders based on etiology and pathophysiology.

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References

  1. Sullivan PF, Neale MC, Kendler KS . Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000; 157: 1552–1562.

    Article  CAS  PubMed  Google Scholar 

  2. Wellcome Trust Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 2007; 447: 661–678.

    Article  CAS  Google Scholar 

  3. Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK . Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry 2006; 60: 93–105.

    Article  PubMed  Google Scholar 

  4. Hasler G, Drevets WC, Manji HK, Charney DS . Discovering endophenotypes for major depression. Neuropsychopharmacology 2004; 29: 1765–1781.

    Article  CAS  PubMed  Google Scholar 

  5. Gottesman II, Shields J . Genetic theorizing and schizophrenia. Br J Psychiatry 1973; 122: 15–30.

    Article  CAS  PubMed  Google Scholar 

  6. Gottesman II, Gould TD . The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636–645.

    Article  PubMed  Google Scholar 

  7. Preston GA, Weinberger DR . Intermediate phenotypes in schizophrenia: a selective review. Dialogues Clin Neurosci 2005; 7: 165–179.

    PubMed  PubMed Central  Google Scholar 

  8. Flint J, Munafo MR . The endophenotype concept in psychiatric genetics. Psychol Med 2007; 37: 163–180.

    Article  PubMed  Google Scholar 

  9. Petty F, Sherman AD . Plasma GABA levels in psychiatric illness. J Affect Disord 1984; 6: 131–138.

    Article  CAS  PubMed  Google Scholar 

  10. Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OA et al. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999; 56: 1043–1047.

    Article  CAS  PubMed  Google Scholar 

  11. Sanacora G, Gueorguieva R, Epperson CN, Wu YT, Appel M, Rothman DL et al. Subtype-specific alterations of gamma-aminobutyric acid and glutamate in patients with major depression. Arch Gen Psychiatry 2004; 61: 705–713.

    Article  CAS  PubMed  Google Scholar 

  12. Hasler G, van der Veen JW, Tumonis T, Meyers N, Shen J, Drevets WC . Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy. Arch Gen Psychiatry 2007; 64: 193–200.

    Article  CAS  PubMed  Google Scholar 

  13. Kaufman RE, Ostacher MJ, Marks EH, Simon NM, Sachs GS, Jensen JE et al. Brain GABA levels in patients with bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 427–434.

    Article  CAS  PubMed  Google Scholar 

  14. Tayoshi S, Nakataki M, Sumitani S, Taniguchi K, Shibuya-Tayoshi S, Numata S et al. GABA concentration in schizophrenia patients and the effects of antipsychotic medication: a proton magnetic resonance spectroscopy study. Schizophr Res 2010; 117: 83–91.

    Article  PubMed  Google Scholar 

  15. Ongur D, Prescot AP, McCarthy J, Cohen BM, Renshaw PF . Elevated gamma-aminobutyric Acid levels in chronic schizophrenia. Biol Psychiatry 2010; 68: 667–670.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Goddard AW, Mason GF, Almai A, Rothman DL, Behar KL, Petroff OA et al. Reductions in occipital cortex GABA levels in panic disorder detected with 1h-magnetic resonance spectroscopy. Arch Gen Psychiatry 2001; 58: 556–561.

    Article  CAS  PubMed  Google Scholar 

  17. Hasler G, van der Veen JW, Geraci M, Shen J, Pine D, Drevets WC . Prefrontal cortical gamma-aminobutyric acid levels in panic disorder determined by proton magnetic resonance spectroscopy. Biol Psychiatry 2009; 65: 273–275.

    Article  CAS  PubMed  Google Scholar 

  18. Behar KL, Rothman DL, Petersen KF, Hooten M, Delaney R, Petroff OA et al. Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients. Am J Psychiatry 1999; 156: 952–954.

    Article  CAS  PubMed  Google Scholar 

  19. Sanacora G, Mason GF, Rothman DL, Hyder F, Ciarcia JJ, Ostroff RB et al. Increased cortical GABA concentrations in depressed patients receiving ECT. Am J Psychiatry 2003; 160: 577–579.

    Article  PubMed  Google Scholar 

  20. Hasler G, van der Veen JW, Grillon C, Drevets W, Shen J . Effect of acute psychological stress on prefrontal gamma-aminobutyric acid concentration determined by proton magnetic resonance spectroscopy. Am J Psychiatry 2010; 167: 1226–1231.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Otero Losada ME . Changes in central GABAergic function following acute and repeated stress. Br J Pharmacol 1988; 93: 483–490.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hasler G, Neumeister A, van der Veen JW, Tumonis T, Bain EE, Shen J et al. Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy. Biol Psychiatry 2005; 58: 969–973.

    Article  CAS  PubMed  Google Scholar 

  23. Bhagwagar Z, Wylezinska M, Jezzard P, Evans J, Ashworth F, Sule A et al. Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects. Biol Psychiatry 2007; 61: 806–812.

    Article  CAS  PubMed  Google Scholar 

  24. Petty F, Steinberg J, Kramer GL, Fulton M, Moeller FG . Desipramine does not alter plasma GABA in patients with major depression. J Affect Disord 1993; 29: 53–56.

    Article  CAS  PubMed  Google Scholar 

  25. Petty F, Kramer GL, Fulton M, Davis L, Rush AJ . Stability of plasma GABA at four-year follow-up in patients with primary unipolar depression. Biol Psychiatry 1995; 37: 806–810.

    Article  CAS  PubMed  Google Scholar 

  26. Alcaro A, Panksepp J, Witczak J, Hayes DJ, Northoff G . Is subcortical-cortical midline activity in depression mediated by glutamate and GABA?A cross-species translational approach. Neurosci Biobehav Rev 2010; 34: 592–605.

    Article  CAS  PubMed  Google Scholar 

  27. Caspi A, Hariri AR, Holmes A, Uher R, Moffitt TE . Genetic sensitivity to the environment: the case of the serotonin transporter gene and its implications for studying complex diseases and traits. Am J Psychiatry 2010; 167: 509–527.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kendler KS, Thornton LM, Gardner CO . Stressful life events and previous episodes in the etiology of major depression in women: an evaluation of the ‘kindling’ hypothesis. Am J Psychiatry 2000; 157: 1243–1251.

    Article  CAS  PubMed  Google Scholar 

  29. Sheline YI, Gado MH, Kraemer HC . Untreated depression and hippocampal volume loss. Am J Psychiatry 2003; 160: 1516–1518.

    Article  PubMed  Google Scholar 

  30. Hasler G, Fromm S, Alvarez RP, Luckenbaugh DA, Drevets WC, Grillon C . Cerebral blood flow in immediate and sustained anxiety. J Neurosci 2007; 27: 6313–6319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Frodl TS, Koutsouleris N, Bottlender R, Born C, Jager M, Scupin I et al. Depression-related variation in brain morphology over 3 years: effects of stress? Arch Gen Psychiatry 2008; 65: 1156–1165.

    Article  PubMed  Google Scholar 

  32. Kendler KS, Thornton LM, Prescott CA . Gender differences in the rates of exposure to stressful life events and sensitivity to their depressogenic effects. Am J Psychiatry 2001; 158: 587–593.

    CAS  PubMed  Google Scholar 

  33. de Groote L, Linthorst AC . Exposure to novelty and forced swimming evoke stressor-dependent changes in extracellular GABA in the rat hippocampus. Neuroscience 2007; 148: 794–805.

    Article  CAS  PubMed  Google Scholar 

  34. Acosta GB, Otero Losada ME, Rubio MC . Area-dependent changes in GABAergic function after acute and chronic cold stress. Neurosci Lett 1993; 154: 175–178.

    Article  CAS  PubMed  Google Scholar 

  35. Gronli J, Fiske E, Murison R, Bjorvatn B, Sorensen E, Ursin R et al. Extracellular levels of serotonin and GABA in the hippocampus after chronic mild stress in rats. A microdialysis study in an animal model of depression. Behav Brain Res 2007; 181: 42–51.

    Article  PubMed  CAS  Google Scholar 

  36. Hasler G, Nugent AC, Carlson PJ, Carson RE, Geraci M, Drevets WC . Altered cerebral GABAA-benzodiazepine receptor binding in panic disorder determined by [11C]flumazenil PET. Arch Gen Psychiatry 2008; 65: 1166–1175.

    Article  PubMed  Google Scholar 

  37. Acosta GB, Rubio MC . GABAA receptors mediate the changes produced by stress on GABA function and locomotor activity. Neurosci Lett 1994; 176: 29–31.

    Article  CAS  PubMed  Google Scholar 

  38. Cullinan WE, Wolfe TJ . Chronic stress regulates levels of mRNA transcripts encoding beta subunits of the GABA(A) receptor in the rat stress axis. Brain Res 2000; 887: 118–124.

    Article  CAS  PubMed  Google Scholar 

  39. Dennis T, Beauchemin V, Lavoie N . Differential effects of olfactory bulbectomy on GABAA and GABAB receptors in the rat brain. Pharmacol Biochem Behav 1993; 46: 77–82.

    Article  CAS  PubMed  Google Scholar 

  40. Drugan RC, Morrow AL, Weizman R, Weizman A, Deutsch SI, Crawley JN et al. Stress-induced behavioral depression in the rat is associated with a decrease in GABA receptor-mediated chloride ion flux and brain benzodiazepine receptor occupancy. Brain Res 1989; 487: 45–51.

    Article  CAS  PubMed  Google Scholar 

  41. Longone P, Rupprecht R, Manieri GA, Bernardi G, Romeo E, Pasini A . The complex roles of neurosteroids in depression and anxiety disorders. Neurochem Int 2008; 52: 596–601.

    Article  CAS  PubMed  Google Scholar 

  42. Klumpers UM, Veltman DJ, Boellaard R, Comans EF, Zuketto C, Yaqub M et al. Comparison of plasma input and reference tissue models for analysing [(11)C] flumazenil studies. J Cereb Blood Flow Metab 2007; 28: 579–587.

    Article  PubMed  CAS  Google Scholar 

  43. Bjork JM, Moeller FG, Kramer GL, Kram M, Suris A, Rush AJ et al. Plasma GABA levels correlate with aggressiveness in relatives of patients with unipolar depressive disorder. Psychiatry Res 2001; 101: 131–136.

    Article  CAS  PubMed  Google Scholar 

  44. McCarthy MM, Auger AP, Perrot-Sinal TS . Getting excited about GABA and sex differences in the brain. Trends Neurosci 2002; 25: 307–312.

    Article  CAS  PubMed  Google Scholar 

  45. Searles RV, Yoo MJ, He JR, Shen WB, Selmanoff M . Sex differences in GABA turnover and glutamic acid decarboxylase (GAD(65) and GAD(67)) mRNA in the rat hypothalamus. Brain Res 2000; 878: 11–19.

    Article  CAS  PubMed  Google Scholar 

  46. Wilson MA, Biscardi R . Sex differences in GABA/benzodiazepine receptor changes and corticosterone release after acute stress in rats. Exp Brain Res 1994; 101: 297–306.

    Article  CAS  PubMed  Google Scholar 

  47. Skilbeck KJ, Hinton T, Johnston GA . Sex-differences and stress: effects on regional high and low affinity [3H]GABA binding. Neurochem Int 2008; 52: 1212–1219.

    Article  CAS  PubMed  Google Scholar 

  48. Shen J . (13)C magnetic resonance spectroscopy studies of alterations in glutamate neurotransmission. Biol Psychiatry 2005; 59: 883–887.

    Article  PubMed  CAS  Google Scholar 

  49. Nutt DJ, Glue P, Lawson C, Wilson S . Flumazenil provocation of panic attacks. Evidence for altered benzodiazepine receptor sensitivity in panic disorder. Arch Gen Psychiatry 1990; 47: 917–925.

    Article  CAS  PubMed  Google Scholar 

  50. Fish EW, Faccidomo S, DeBold JF, Miczek KA . Alcohol, allopregnanolone and aggression in mice. Psychopharmacology (Berl) 2001; 153: 473–483.

    Article  CAS  Google Scholar 

  51. Sustkova-Fiserova M, Vavrova J, Krsiak M . Brain levels of GABA, glutamate and aspartate in sociable, aggressive and timid mice: an in vivo microdialysis study. Neuro Endocrinol Lett 2009; 30: 79–84.

    CAS  PubMed  Google Scholar 

  52. Hoffman DA . Tiagabine for rage, aggression, and anxiety. J Neuropsychiatry Clin Neurosci 2005 Spring 17: 252.

    Article  PubMed  Google Scholar 

  53. Reynolds SM, Berridge KC . Positive and negative motivation in nucleus accumbens shell: bivalent rostrocaudal gradients for GABA-elicited eating, taste ‘liking’/‘disliking’ reactions, place preference/avoidance, and fear. J Neurosci 2002; 22: 7308–7320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gureje O, Oladeji B, Hwang I, Chiu WT, Kessler RC, Sampson NA et al. Parental psychopathology and the risk of suicidal behavior in their offspring: results from the World Mental Health surveys. Mol Psychiatry 2011 (in press).

  55. Merali Z, Du L, Hrdina P, Palkovits M, Faludi G, Poulter MO et al. Dysregulation in the suicide brain: mRNA expression of corticotropin-releasing hormone receptors and GABA(A) receptor subunits in frontal cortical brain region. J Neurosci 2004; 24: 1478–1485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Poulter MO, Du L, Zhurov V, Palkovits M, Faludi G, Merali Z et al. Altered organization of GABA(A) receptor mRNA expression in the depressed suicide brain. Front Mol Neurosci 2010; 3: 3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Poulter MO, Du L, Weaver IC, Palkovits M, Faludi G, Merali Z et al. GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes. Biol Psychiatry 2008; 64: 645–652.

    Article  CAS  PubMed  Google Scholar 

  58. Dong E, Agis-Balboa RC, Simonini MV, Grayson DR, Costa E, Guidotti A . Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. Proc Natl Acad Sci USA 2005; 102: 12578–12583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tunnicliff G . 4-aminobutyrate transaminase. In: Boulton AA, Baker GB, Yu PH (eds). Neurotransmitter Enzymes. Humana Press: Clifton, NJ, 1986.

    Google Scholar 

  60. Petty F, Fulton M, Kramer GL, Kram M, Davis LL, Rush AJ . Evidence for the segregation of a major gene for human plasma GABA levels. Mol Psychiatry 1999; 4: 587–589.

    Article  CAS  PubMed  Google Scholar 

  61. Petty F, Schlesser MA . Plasma GABA in affective illness. A preliminary investigation. J Affect Disord 1981; 3: 339–343.

    Article  CAS  PubMed  Google Scholar 

  62. Bhagwagar Z, Wylezinska M, Taylor M, Jezzard P, Matthews PM, Cowen PJ . Increased brain GABA concentrations following acute administration of a selective serotonin reuptake inhibitor. Am J Psychiatry 2004; 161: 368–370.

    Article  PubMed  Google Scholar 

  63. Kendler KS, Neale MC . Endophenotype: a conceptual analysis. Mol Psychiatry 2010; 15: 789–797.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Asada H, Kawamura Y, Maruyama K, Kume H, Ding RG, Kanbara N et al. Cleft palate and decreased brain gamma-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 1997; 94: 6496–6499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hettema JM, An SS, Neale MC, Bukszar J, Van den Oord EJ, Kendler KS et al. Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism. Mol Psychiatry 2006; 11: 752–762.

    Article  CAS  PubMed  Google Scholar 

  66. Marenco S, Savostyanova AA, Van der Veen JW, Geramita M, Stern A, Barnett AS et al. Genetic modulation of GABA levels in the anterior cingulate cortex by GAD1 and COMT. Neuropsychopharmacology 2010; 35: 1708–1717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Karolewicz B, Maciag D, O’Dwyer G, Stockmeier CA, Feyissa AM, Rajkowska G . Reduced level of glutamic acid decarboxylase-67 kDa in the prefrontal cortex in major depression. Int J Neuropsychopharmacol 2010; 13: 411–420.

    Article  CAS  PubMed  Google Scholar 

  68. Maciag D, Hughes J, O’Dwyer G, Pride Y, Stockmeier CA, Sanacora G et al. Reduced density of calbindin immunoreactive GABAergic neurons in the occipital cortex in major depression: relevance to neuroimaging studies. Biol Psychiatry 2010; 67: 465–470.

    Article  CAS  PubMed  Google Scholar 

  69. Rajkowska G, O’Dwyer G, Teleki Z, Stockmeier CA, Miguel-Hidalgo JJ . GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression. Neuropsychopharmacology 2007; 32: 471–482.

    Article  CAS  PubMed  Google Scholar 

  70. Skilbeck KJ, Johnston GA, Hinton T . Stress and GABA receptors. J Neurochem 2010; 112: 1115–1130.

    Article  CAS  PubMed  Google Scholar 

  71. Sen S, Villafuerte S, Nesse R, Stoltenberg SF, Hopcian J, Gleiberman L et al. Serotonin transporter and GABAA alpha 6 receptor variants are associated with neuroticism. Biol Psychiatry 2004; 55: 244–249.

    Article  CAS  PubMed  Google Scholar 

  72. Oruc L, Verheyen GR, Furac I, Ivezic S, Jakovljevic M, Raeymaekers P et al. Positive association between the GABRA5 gene and unipolar recurrent major depression. Neuropsychobiology 1997; 36: 62–64.

    Article  CAS  PubMed  Google Scholar 

  73. Yamada K, Watanabe A, Iwayama-Shigeno Y, Yoshikawa T . Evidence of association between gamma-aminobutyric acid type A receptor genes located on 5q34 and female patients with mood disorders. Neurosci Lett 2003; 349: 9–12.

    Article  CAS  PubMed  Google Scholar 

  74. Horiuchi Y, Nakayama J, Ishiguro H, Ohtsuki T, Detera-Wadleigh SD, Toyota T et al. Possible association between a haplotype of the GABA-A receptor alpha 1 subunit gene (GABRA1) and mood disorders. Biol Psychiatry 2004; 55: 40–45.

    Article  CAS  PubMed  Google Scholar 

  75. Henkel V, Baghai TC, Eser D, Zill P, Mergl R, Zwanzger P et al. The gamma amino butyric acid (GABA) receptor alpha-3 subunit gene polymorphism in unipolar depressive disorder: a genetic association study. Am J Med Genet B Neuropsychiatr Genet 2004; 126B: 82–87.

    Article  PubMed  Google Scholar 

  76. Ciranna L . Serotonin as a modulator of glutamate-and GABA-mediated neurotransmission: implications in physiological functions and in pathology. Curr Neuropharmacol 2006; 4: 101–114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. McMahon LL, Kauer JA . Hippocampal interneurons are excited via serotonin-gated ion channels. J Neurophysiol 1997; 78: 2493–2502.

    Article  CAS  PubMed  Google Scholar 

  78. Shen RY, Andrade R . 5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus. J Pharmacol Exp Ther 1998; 285: 805–812.

    CAS  PubMed  Google Scholar 

  79. Khan ZU, Gutierrez A, Martin R, Penafiel A, Rivera A, De La Calle A . Differential regional and cellular distribution of dopamine D2-like receptors: an immunocytochemical study of subtype-specific antibodies in rat and human brain. J Comp Neurol 1998; 402: 353–371.

    Article  CAS  PubMed  Google Scholar 

  80. Delgado A, Sierra A, Querejeta E, Valdiosera RF, Aceves J . Inhibitory control of the GABAergic transmission in the rat neostriatum by D2 dopamine receptors. Neuroscience 2000; 95: 1043–1048.

    Article  CAS  PubMed  Google Scholar 

  81. Seamans JK, Gorelova N, Durstewitz D, Yang CR . Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 2001; 21: 3628–3638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lebon V, Petersen KF, Cline GW, Shen J, Mason GF, Dufour S et al. Astroglial contribution to brain energy metabolism in humans revealed by 13C nuclear magnetic resonance spectroscopy: elucidation of the dominant pathway for neurotransmitter glutamate repletion and measurement of astrocytic oxidative metabolism. J Neurosci 2002; 22: 1523–1531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Magistretti PJ, Pellerin L, Rothman DL, Shulman RG . Energy on demand. Science 1999; 283: 496–497.

    Article  CAS  PubMed  Google Scholar 

  84. Auer DP, Putz B, Kraft E, Lipinski B, Schill J, Holsboer F . Reduced glutamate in the anterior cingulate cortex in depression: an in vivo proton magnetic resonance spectroscopy study. Biol Psychiatry 2000; 47: 305–313.

    Article  CAS  PubMed  Google Scholar 

  85. Michael N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B . Metabolic changes within the left dorsolateral prefrontal cortex occurring with electroconvulsive therapy in patients with treatment resistant unipolar depression. Psychol Med 2003; 33: 1277–1284.

    Article  CAS  PubMed  Google Scholar 

  86. Block W, Traber F, Von Widdern O, Metten M, Schild H, Maier W et al. Proton MR spectroscopy of the hippocampus at 3T in patients with unipolar major depressive disorder: correlates and predictors of treatment response. Int J Neuropsychopharmacol 2009; 12: 415–422.

    Article  CAS  PubMed  Google Scholar 

  87. Walter M, Henning A, Grimm S, Schulte RF, Beck J, Dydak U et al. The relationship between aberrant neuronal activation in the pregenual anterior cingulate, altered glutamatergic metabolism, and anhedonia in major depression. Arch Gen Psychiatry 2009; 66: 478–486.

    Article  CAS  PubMed  Google Scholar 

  88. Milne A, MacQueen GM, Yucel K, Soreni N, Hall GB . Hippocampal metabolic abnormalities at first onset and with recurrent episodes of a major depressive disorder: a proton magnetic resonance spectroscopy study. Neuroimage 2009; 47: 36–41.

    Article  PubMed  Google Scholar 

  89. Price RB, Shungu DC, Mao X, Nestadt P, Kelly C, Collins KA et al. Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: relationship to treatment resistance in major depressive disorder. Biol Psychiatry 2009; 65: 792–800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hashimoto K . Emerging role of glutamate in the pathophysiology of major depressive disorder. Brain Res Rev 2009; 61: 105–123.

    Article  CAS  PubMed  Google Scholar 

  91. Machado-Vieira R, Manji HK, Zarate CA . The role of the tripartite glutamatergic synapse in the pathophysiology and therapeutics of mood disorders. Neuroscientist 2009; 15: 525–539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Yuksel C, Ongur D . Magnetic resonance spectroscopy studies of glutamate-related abnormalities in mood disorders. Biol Psychiatry 2010; 68: 785–794.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Michael N, Erfurth A, Ohrmann P, Arolt V, Heindel W, Pfleiderer B . Neurotrophic effects of electroconvulsive therapy: a proton magnetic resonance study of the left amygdalar region in patients with treatment-resistant depression. Neuropsychopharmacology 2003; 28: 720–725.

    Article  CAS  PubMed  Google Scholar 

  94. Pfleiderer B, Michael N, Erfurth A, Ohrmann P, Hohmann U, Wolgast M et al. Effective electroconvulsive therapy reverses glutamate/glutamine deficit in the left anterior cingulum of unipolar depressed patients. Psychiatry Res 2003; 122: 185–192.

    Article  CAS  PubMed  Google Scholar 

  95. Moghaddam B . Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. Biol Psychiatry 2002; 51: 775–787.

    Article  CAS  PubMed  Google Scholar 

  96. Bagley J, Moghaddam B . Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam. Neuroscience 1997; 77: 65–73.

    Article  CAS  PubMed  Google Scholar 

  97. Gao SF, Bao AM . Corticotropin-releasing hormone, glutamate, and {gamma}-aminobutyric acid in depression. Neuroscientist 2011; 17: 124–144.

    Article  CAS  PubMed  Google Scholar 

  98. Grace AA . Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res Brain Res Rev 2000; 31: 330–341.

    Article  CAS  PubMed  Google Scholar 

  99. Sesack SR, Carr DB, Omelchenko N, Pinto A . Anatomical substrates for glutamate-dopamine interactions: evidence for specificity of connections and extrasynaptic actions. Ann N Y Acad Sci 2003; 1003: 36–52.

    Article  CAS  PubMed  Google Scholar 

  100. Rajkowska G, Miguel-Hidalgo JJ . Gliogenesis and glial pathology in depression. CNS Neurol Disord Drug Targets 2007; 6: 219–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Lyoo IK, Yoon SJ, Musen G, Simonson DC, Weinger K, Bolo N et al. Altered prefrontal glutamate-glutamine-gamma-aminobutyric acid levels and relation to low cognitive performance and depressive symptoms in type 1 diabetes mellitus. Arch Gen Psychiatry 2009; 66: 878–887.

    Article  CAS  PubMed  Google Scholar 

  102. Choudary PV, Molnar M, Evans SJ, Tomita H, Li JZ, Vawter MP et al. Altered cortical glutamatergic and GABAergic signal transmission with glial involvement in depression. Proc Natl Acad Sci USA 2005; 102: 15653–15658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Bernard R, Kerman IA, Thompson RC, Jones EG, Bunney WE, Barchas JD et al. Altered expression of glutamate signaling, growth factor, and glia genes in the locus coeruleus of patients with major depression. Mol Psychiatry 2011 (in press).

  104. McCullumsmith RE, Meador-Woodruff JH . Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. Neuropsychopharmacology 2002; 26: 368–375.

    Article  CAS  PubMed  Google Scholar 

  105. Tordera RM, Totterdell S, Wojcik SM, Brose N, Elizalde N, Lasheras B et al. Enhanced anxiety, depressive-like behaviour and impaired recognition memory in mice with reduced expression of the vesicular glutamate transporter 1 (VGLUT1). Eur J Neurosci 2007; 25: 281–290.

    Article  CAS  PubMed  Google Scholar 

  106. Zink M, Vollmayr B, Gebicke-Haerter PJ, Henn FA . Reduced expression of glutamate transporters vGluT1, EAAT2 and EAAT4 in learned helpless rats, an animal model of depression. Neuropharmacology 2010; 58: 465–473.

    Article  CAS  PubMed  Google Scholar 

  107. Chourbaji S, Vogt MA, Fumagalli F, Sohr R, Frasca A, Brandwein C et al. AMPA receptor subunit 1 (GluR-A) knockout mice model the glutamate hypothesis of depression. FASEB J 2008; 22: 3129–3134.

    Article  CAS  PubMed  Google Scholar 

  108. Boyce-Rustay JM, Holmes A . Genetic inactivation of the NMDA receptor NR2A subunit has anxiolytic-and antidepressant-like effects in mice. Neuropsychopharmacology 2006; 31: 2405–2414.

    Article  CAS  PubMed  Google Scholar 

  109. Beneyto M, Kristiansen LV, Oni-Orisan A, McCullumsmith RE, Meador-Woodruff JH . Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 2007; 32: 1888–1902.

    Article  CAS  PubMed  Google Scholar 

  110. Feyissa AM, Chandran A, Stockmeier CA, Karolewicz B . Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 70–75.

    Article  CAS  PubMed  Google Scholar 

  111. Matrisciano F, Caruso A, Orlando R, Marchiafava M, Bruno V, Battaglia G et al. Defective group-II metaboropic glutamate receptors in the hippocampus of spontaneously depressed rats. Neuropharmacology 2008; 55: 525–531.

    Article  CAS  PubMed  Google Scholar 

  112. Wieronska JM, Branski P, Szewczyk B, Palucha A, Papp M, Gruca P et al. Changes in the expression of metabotropic glutamate receptor 5 (mGluR5) in the rat hippocampus in an animal model of depression. Pol J Pharmacol 2001; 53: 659–662.

    CAS  PubMed  Google Scholar 

  113. Shen J . 13C magnetic resonance spectroscopy studies of alterations in glutamate neurotransmission. Biol Psychiatry 2006; 59: 883–887.

    CAS  PubMed  Google Scholar 

  114. Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL . A default mode of brain function. Proc Natl Acad Sci USA 2001; 98: 676–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Phillips ML, Drevets WC, Rauch SL, Lane R . Neurobiology of emotion perception II: implications for major psychiatric disorders. Biol Psychiatry 2003; 54: 515–528.

    Article  PubMed  Google Scholar 

  116. Mayberg HS . Positron emission tomography imaging in depression: a neural systems perspective. Neuroimaging Clin N Am 2003; 13: 805–815.

    Article  PubMed  Google Scholar 

  117. Mayberg HS . Modulating limbic-cortical circuits in depression: targets of antidepressant treatments. Semin Clin Neuropsychiatry 2002; 7: 255–268.

    Article  PubMed  Google Scholar 

  118. Mayberg HS . Targeted electrode-based modulation of neural circuits for depression. J Clin Invest 2009; 119: 717–725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Savitz JB, Drevets WC . Imaging phenotypes of major depressive disorder: genetic correlates. Neuroscience 2009; 164: 300–330.

    Article  CAS  PubMed  Google Scholar 

  120. Fitzgerald PB, Laird AR, Maller J, Daskalakis ZJ . A meta-analytic study of changes in brain activation in depression. Hum Brain Mapp 2008; 29: 683–695.

    Article  PubMed  Google Scholar 

  121. Price JL, Drevets WC . Neurocircuitry of mood disorders. Neuropsychopharmacology 2009; 35: 192–216.

    Article  PubMed Central  Google Scholar 

  122. Drevets WC, Price JL, Furey ML . Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct 2008; 213: 93–118.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Savitz J, Drevets WC . Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide. Neurosci Biobehav Rev 2009; 33: 699–771.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Grimm S, Boesiger P, Beck J, Schuepbach D, Bermpohl F, Walter M et al. Altered negative BOLD responses in the default-mode network during emotion processing in depressed subjects. Neuropsychopharmacology 2009; 34: 932–843.

    Article  PubMed  Google Scholar 

  125. Hasler G, Fromm S, Carlson PJ, Luckenbaugh DA, Waldeck T, Geraci M et al. Neural response to catecholamine depletion in unmedicated subjects with major depressive disorder in remission and healthy subjects. Arch Gen Psychiatry 2008; 65: 521–531.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Northoff G . Psychopathology and pathophysiology of the self in depression-neuropsychiatric hypothesis. J Affect Disord 2007; 104: 1–14.

    Article  PubMed  Google Scholar 

  127. Lemogne C, Gorwood P, Bergouignan L, Pelissolo A, Lehericy S, Fossati P . Negative affectivity, self-referential processing and the cortical midline structures. Soc Cogn Affect Neurosci 2011 (in press).

  128. Lemogne C, le Bastard G, Mayberg H, Volle E, Bergouignan L, Lehericy S et al. In search of the depressive self: extended medial prefrontal network during self-referential processing in major depression. Soc Cogn Affect Neurosci 2009; 4: 305–312.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Grimm S, Ernst J, Boesiger P, Schuepbach D, Hell D, Boeker H et al. Increased self-focus in major depressive disorder is related to neural abnormalities in subcortical-cortical midline structures. Hum Brain Mapp 2009; 30: 2617–2627.

    Article  PubMed  Google Scholar 

  130. Northoff G, Heinzel A, de Greck M, Bermpohl F, Dobrowolny H, Panksepp J . Self-referential processing in our brain--a meta-analysis of imaging studies on the self. Neuroimage 2006; 31: 440–457.

    Article  PubMed  Google Scholar 

  131. Enzi B, de Greck M, Prosch U, Tempelmann C, Northoff G . Is our self nothing but reward? Neuronal overlap and distinction between reward and personal relevance and its relation to human personality. PLoS One 2009; 4: e8429.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Northoff G, Walter M, Schulte RF, Beck J, Dydak U, Henning A et al. GABA concentrations in the human anterior cingulate cortex predict negative BOLD responses in fMRI. Nat Neurosci 2007; 10: 1515–1517.

    Article  CAS  PubMed  Google Scholar 

  133. Muthukumaraswamy SD, Edden RA, Jones DK, Swettenham JB, Singh KD . Resting GABA concentration predicts peak gamma frequency and fMRI amplitude in response to visual stimulation in humans. Proc Natl Acad Sci USA 2009; 106: 8356–8361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Northoff G, Qin P, Nakao T . Rest-stimulus interaction in the brain: a review. Trends Neurosci 2010; 33: 277–284.

    Article  CAS  PubMed  Google Scholar 

  135. Levinson AJ, Fitzgerald PB, Favalli G, Blumberger DM, Daigle M, Daskalakis ZJ . Evidence of cortical inhibitory deficits in major depressive disorder. Biol Psychiatry 2010; 67: 458–464.

    Article  CAS  PubMed  Google Scholar 

  136. Bajbouj M, Lang UE, Neu P, Heuser I . Therapeutic brain stimulation and cortical excitability in depressed patients. Am J Psychiatry 2005; 162: 2192–2193.

    Article  PubMed  Google Scholar 

  137. Sanacora G . Cortical inhibition, gamma-aminobutyric acid, and major depression: there is plenty of smoke but is there fire? Biol Psychiatry 2010; 67: 397–398.

    Article  PubMed  Google Scholar 

  138. Morgane PJ, Galler JR, Mokler DJ . A review of systems and networks of the limbic forebrain/limbic midbrain. Prog Neurobiol 2005; 75: 143–160.

    Article  PubMed  Google Scholar 

  139. Meyer-Lindenberg A . Neural connectivity as an intermediate phenotype: brain networks under genetic control. Hum Brain Mapp 2009; 30: 1938–1946.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Meyer-Lindenberg A, Weinberger DR . Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 2006; 7: 818–827.

    Article  CAS  PubMed  Google Scholar 

  141. Meyer-Lindenberg AS, Olsen RK, Kohn PD, Brown T, Egan MF, Weinberger DR et al. Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry 2005; 62: 379–386.

    Article  PubMed  Google Scholar 

  142. Esslinger C, Walter H, Kirsch P, Erk S, Schnell K, Arnold C et al. Neural mechanisms of a genome-wide supported psychosis variant. Science 2009; 324: 605.

    Article  CAS  PubMed  Google Scholar 

  143. Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L et al. Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study. Biol Psychiatry 2005; 57: 1079–1088.

    Article  PubMed  Google Scholar 

  144. Anand A, Li Y, Wang Y, Lowe MJ, Dzemidzic M . Resting state corticolimbic connectivity abnormalities in unmedicated bipolar disorder and unipolar depression. Psychiatry Res 2009; 171: 189–198.

    Article  PubMed  PubMed Central  Google Scholar 

  145. Bluhm R, Williamson P, Lanius R, Theberge J, Densmore M, Bartha R et al. Resting state default-mode network connectivity in early depression using a seed region-of-interest analysis: decreased connectivity with caudate nucleus. Psychiatry Clin Neurosci 2009; 63: 754–761.

    Article  PubMed  Google Scholar 

  146. Seminowicz DA, Mayberg HS, McIntosh AR, Goldapple K, Kennedy S, Segal Z et al. Limbic-frontal circuitry in major depression: a path modeling metanalysis. Neuroimage 2004; 22: 409–418.

    Article  CAS  PubMed  Google Scholar 

  147. James GA, Kelley ME, Craddock RC, Holtzheimer PE, Dunlop BW, Nemeroff CB et al. Exploratory structural equation modeling of resting-state fMRI: applicability of group models to individual subjects. Neuroimage 2009; 45: 778–787.

    Article  PubMed  Google Scholar 

  148. Sheline YI, Price JL, Yan Z, Mintun MA . Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus. Proc Natl Acad Sci USA 2010; 107: 11020–11025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Zhou Y, Yu C, Zheng H, Liu Y, Song M, Qin W et al. Increased neural resources recruitment in the intrinsic organization in major depression. J Affect Disord 2010; 121: 220–230.

    Article  PubMed  Google Scholar 

  150. Horn DI, Yu C, Steiner J, Buchmann J, Kaufmann J, Osoba A et al. Glutamatergic and resting-state functional connectivity correlates of severity in major depression-the role of pregenual anterior cingulate cortex and anterior insula. Front Syst Neurosci 2010; 4: 1–10.

    Google Scholar 

  151. Greicius MD, Flores BH, Menon V, Glover GH, Solvason HB, Kenna H et al. Resting-state functional connectivity in major depression: abnormally increased contributions from subgenual cingulate cortex and thalamus. Biol Psychiatry 2007; 62: 429–437.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Johansen-Berg H, Gutman DA, Behrens TE, Matthews PM, Rushworth MF, Katz E et al. Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression. Cereb Cortex 2008; 18: 1374–1383.

    Article  CAS  PubMed  Google Scholar 

  153. Hamilton JP, Chen G, Thomason ME, Schwartz ME, Gotlib IH . Investigating neural primacy in major depressive disorder: multivariate granger causality analysis of resting-state fMRI time-series data. Mol Psychiatry 2011 (in press).

  154. Greicius MD, Supekar K, Menon V, Dougherty RF . Resting-state functional connectivity reflects structural connectivity in the default mode network. Cereb Cortex 2009; 19: 72–78.

    Article  PubMed  Google Scholar 

  155. Glahn DC, Winkler AM, Kochunov P, Almasy L, Duggirala R, Carless MA et al. Genetic control over the resting brain. Proc Natl Acad Sci USA 2010; 107: 1223–1228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Liu Z, Xu C, Xu Y, Wang Y, Zhao B, Lv Y et al. Decreased regional homogeneity in insula and cerebellum: a resting-state fMRI study in patients with major depression and subjects at high risk for major depression. Psychiatry Res 2010; 182: 211–215.

    Article  PubMed  Google Scholar 

  157. Northoff G, Kotter R, Baumgart F, Danos P, Boeker H, Kaulisch T et al. Orbitofrontal cortical dysfunction in akinetic catatonia: a functional magnetic resonance imaging study during negative emotional stimulation. Schizophr Bull 2004; 30: 405–427.

    Article  PubMed  Google Scholar 

  158. Frodl T, Bokde AL, Scheuerecker J, Lisiecka D, Schoepf V, Hampel H et al. Functional connectivity bias of the orbitofrontal cortex in drug-free patients with major depression. Biol Psychiatry 2010; 67: 161–167.

    Article  PubMed  Google Scholar 

  159. Hamilton JP, Gotlib IH . Neural substrates of increased memory sensitivity for negative stimuli in major depression. Biol Psychiatry 2008; 63: 1155–1162.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Yoshimura S, Ueda K, Suzuki S, Onoda K, Okamoto Y, Yamawaki S . Self-referential processing of negative stimuli within the ventral anterior cingulate gyrus and right amygdala. Brain Cogn 2009; 69: 218–225.

    Article  PubMed  Google Scholar 

  161. Schlosser RG, Wagner G, Koch K, Dahnke R, Reichenbach JR, Sauer H . Fronto-cingulate effective connectivity in major depression: a study with fMRI and dynamic causal modeling. Neuroimage 2008; 43: 645–655.

    Article  CAS  PubMed  Google Scholar 

  162. Vasic N, Walter H, Sambataro F, Wolf RC . Aberrant functional connectivity of dorsolateral prefrontal and cingulate networks in patients with major depression during working memory processing. Psychol Med 2009; 39: 977–987.

    Article  CAS  PubMed  Google Scholar 

  163. Salvadore G, Cornwell BR, Sambataro F, Latov D, Colon-Rosario V, Carver F et al. Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine. Neuropsychopharmacology 2010; 35: 1415–1422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Friedel E, Schlagenhauf F, Sterzer P, Park SQ, Bermpohl F, Strohle A et al. 5-HTT genotype effect on prefrontal-amygdala coupling differs between major depression and controls. Psychopharmacology (Berl) 2009; 205: 261–271.

    Article  CAS  Google Scholar 

  165. Chamberlain SR, Sahakian BJ . The neuropsychology of mood disorders. Curr Psychiatry Rep 2006; 8: 458–463.

    Article  PubMed  Google Scholar 

  166. Konopka RJ, Benzer S . Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci USA 1971; 68: 2112–2116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Takahashi JS, Shimomura K, Kumar V . Searching for genes underlying behavior: lessons from circadian rhythms. Science 2008; 322: 909–912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Hasler, G., Northoff, G. Discovering imaging endophenotypes for major depression. Mol Psychiatry 16, 604–619 (2011). https://doi.org/10.1038/mp.2011.23

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