The Subgenual Anterior Cingulate Cortex in Mood Disorders | CNS Spectrums | Cambridge Core (original) (raw)

Abstract

The anterior cingulate cortex (ACC) ventral to the genu of the corpus callosum has been implicated in the modulation of emotional behavior on the basis of neuroimaging studies in humans and lesion analyses in experimental animals. In a combined positron emission tomography/magnetic resonance imaging study of mood disorders, we demonstrated that the mean gray matter volume of this “subgenual” ACC (sgACC) cortex is abnormally reduced in subjects with major depressive disorder (MDD) and bipolar disorder, irrespective of mood state. Neuropathological assessments of sgACC tissue acquired postmortem from subjects with MDD or bipolar disorder confirmed the decrement in gray matter volume, and revealed that this abnormality was associated with a reduction in glia, with no equivalent loss of neurons. In positron emission tomography studies, the metabolic activity was elevated in this region in the depressed relative to the remitted phases of the same MDD subjects, and effective antidepressant treatment was associated with a reduction in sgACC activity. Other laboratories replicated and extended these findings, and the clinical importance of this treatment effect was underscored by a study showing that deep brain stimulation of the sgACC ameliorates depressive symptoms in treatment-resistant MDD. This article discusses the functional significance of these findings within the context of the preclinical literature that implicates the putative homologue of this region in the regulation of emotional behavior and stress response. In experimental animals, this region participates in an extended “visceromotor network” of structures that modulates autonomic/neuroendocrine responses and neurotransmitter transmission during the neural processing of reward, fear, and stress. These data thus hold important implications for the development of neural models of depression that can account for the abnormal motivational, neuroendocrine, autonomic, and emotional manifestations evident in human mood disorders.

References

1.Drevets, WC, Price, JL, Simpson, JR Jr, et al.Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997;386:824–827.CrossRefGoogle ScholarPubMed

2.Mazziotta, JC, Phelps, ME, Plummer, D, Kuhl, DE. Quantitation in positron emission computed tomography: 5. Physical—anatomical effects. J Comput Assist Tomogr. 1981;5:734–743.CrossRefGoogle ScholarPubMed

3.Ongür, D, Drevets, WC, Price, JL. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci USA. 1998;95:13290–13295.CrossRefGoogle ScholarPubMed

4.Ongür, D, Ferry, AT, Price, JL. Architectonic subdivision of the human orbital and medial prefrontal cortex. J Comp Neurol. 2003;460:425–449.CrossRefGoogle ScholarPubMed

5.Botteron, KN, Raichle, ME, Drevets, WC, Heath, AC, Todd, RD. Volumetric reduction in left subgenual prefrontal cortex in early onset depression. Biol Psychiatry. 2002;51:342–344.Google ScholarPubMed

6.Hirayasu, Y, Shenton, ME, Salisbury, DF, et al.Subgenual cingulate cortex volume in first-episode psychosis. Am J Psychiatry. 1999;156:1091–1093.CrossRefGoogle ScholarPubMed

7.Drevets, WC, Ryan, N, Bogers, W, Birmaher, B, Axelson, D, Dahl, R. Subgenual prefrontal cortex volume decreased in healthy humans at high familial risk for mood disorders. Abstract presented at. Annual Meeting Of The Society For Neuroscience. October 23, 2007; San Diego, Calif.Google Scholar

8.Boes, AD, McCormick, LM, Coryell, WH, Nopoulos, P. Rostral anterior cingulate cortex volume correlates with depressed mood in normal healthy children. Biol Psychiatry. 2007;63:391–397.CrossRefGoogle ScholarPubMed

9.Hastings, RS, Parsey, RV, Oquendo, MA, Arango, V, Mann, JJ. Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression. Neuropsychopharmacology. 2004;29:952–959.CrossRefGoogle ScholarPubMed

10.Coryell, W, Nopoulos, P, Drevets, W, Wilson, T, Andreasen, NC. Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: diagnostic specificity and prognostic implications. Am J Psychiatry. 2005;162:1706–1712.CrossRefGoogle ScholarPubMed

11.Adler, CM, DelBello, MP, Jarvis, K, Levine, A, Adams, J, Strakowski, SM. Voxel-based study of structural changes in first-episode patients with bipolar disorder. Biol Psychiatry. 2006;61:776–781.CrossRefGoogle ScholarPubMed

12.Haznedar, MM, Roversi, F, Pallanti, S. Fronto-thalamo-striatal gray and white matter volumes and anisotropy of their connections in bipolar spectrum illnesses. Biol Psychiatry. 2005;57:733–742.CrossRefGoogle ScholarPubMed

13.Drevets, WC, Gadde, K. Krishnan, KRR. Neuroimaging studies of depression. In: Charney, DS, Nestler, EJ, Bunney, BJ, eds. The Neurobiological Foundation Of Mental Illness. 2nd ed. New York, NY: Oxford University Press; 2004:461–490.Google Scholar

14.Drevets, WC, Videen, TO, Price, JL, Preskorn, SH, Carmichael, ST, Raichle, ME. A functional anatomical study of unipolar depression. J Neurosci. 1992;12:3628–3641.CrossRefGoogle ScholarPubMed

15.Wu, J, Buchsbaum, MS, Gillin, JC, et al.Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex. Am J Psychiatry. 1999;156:1149–58.CrossRefGoogle ScholarPubMed

16.Mayberg, HS, Brannan, SK, Tekell, JL, et al.Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response. Biol Psychiatry. 2000;48:830–843.CrossRefGoogle ScholarPubMed

17.Kennedy, SH, Evans, KR, Krüger, S. Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression. Am J Psychiatry. 2001;158:899–905.CrossRefGoogle ScholarPubMed

18.Drevets, WC, Bogers, W, Raichle, ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol. 2002;12:527–544.CrossRefGoogle ScholarPubMed

19.Dunn, RT, Kimbrell, TA, Ketter, TA, et al.Principal components of the Beck Depression Inventory and regional cerebral metabolism in unipolar and bipolar depression. Biol Psychiatry. 2002;51:387–399.CrossRefGoogle ScholarPubMed

20.Liotti, M, Mayberg, HS, McGinnis, S, Brannan, SL, Jerabek, RUnmasking disease-specific cerebral blood flow abnormalities: mood challenge in patients with remitted unipolar depression. Am J Psychiatry. 2002;159:1830–1840.CrossRefGoogle ScholarPubMed

21.Winokur, G, Coryell, W. Familial subtypes of unipolar depression: a prospective study of familial pure depressive disease compared to depression spectrum disease. Biol Psychiatry. 1992;32:1012–1018.CrossRefGoogle ScholarPubMed

22.Smith, GS, Kramer, E, Hermann, CR, et al.Acute and chronic effects of citalopram on cerebral glucose metabolism in geriatric depression. Am J Geriatr Psychiatry. 2002;10:715–723.Google ScholarPubMed

23.Davidson, RJ, Irwin, W, Anderle, MJ, Kalin, NH. The neural substrates of affective processing in depressed patients treated with venlafaxine. Am J Psychiatry. 2003;160:64–75.CrossRefGoogle ScholarPubMed

24.Kegeles, LS, Malone, KM, Slifstein, M, et al.Response of cortical metabolic deficits to serotonergic challenge in familial mood disorders. Am J Psychiatry. 2003;160:76–82.Google ScholarPubMed

25.Holthoff, VA, Beuthien-Baumann, B, Zündorf, G, et al.Changes in brain metabolism associated with remission in unipolar major depression. Acta Psychiatr Scand. 2004;110:184–94.CrossRefGoogle ScholarPubMed

26.Pizzagalli, DA, Oakes, TR, Fox, AS, et al.Functional but not structural subgenual prefrontal cortex abnormalities in melancholia. Mol Psychiatry. 2004;9:325, 393–405.CrossRefGoogle Scholar

27.Gotlib, IH, Sivers, H, Gabrieli, JD, et al.Subgenual anterior cingulate activation to valenced emotional stimuli in major depression. Neuroreport. 2005;16:1731–1734.CrossRefGoogle ScholarPubMed

28.Mayberg, HS, Lozano, AM, Voon, V, et al.Deep brain stimulation for treatment-resistant depression. Neuron. 2005;45:651–660.CrossRefGoogle ScholarPubMed

29.Drevets, W, Spitznagel, E, Raichle, M. Functional anatomical differences between major depressive subtypes. J Cereb Blood Flow Metab. 1995;15:S93Google Scholar

30.Clark, CP, Brown, GG, Frank, L, Thomas, L, Sutherland, AN, Gillin, JC. Improved anatomic delineation of the antidepressant response to partial sleep deprivation in medial frontal cortex using perfusion-weighted functional MRI. Psychiatry Res. 2006;146:213–222.CrossRefGoogle ScholarPubMed

31.Kumano, H, Ida, I, Oshima, A, et al.Brain metabolic changes associated with predispotion to onset of major depressive disorder and adjustment disorder in cancer patients—a preliminary PET study. J Psychiatr Res. 2006;41:591–599.CrossRefGoogle ScholarPubMed

32.Chen, CH, Ridler, K, Suckling, J, et al.Brain imaging correlates of depressive symptom severity and predictors of symptom improvement after antidepressant treatment. Biol Psychiatry. 2007:62:407–414.CrossRefGoogle ScholarPubMed

33.Nahas, Z, Teneback, C, Chae, JH, et al.Serial vagus nerve stimulation functional MRI in treatment-resistant depression. Neuropsychopharmacology. 2007;32:1649–1660.CrossRefGoogle ScholarPubMed

34.Savitz, J, Drevets, WC. Bipolar and Major Depressive Disorder: Neuroimaging the Developmental-Degenerative Divide; Neuroscience and Biobehavioral Reviews, In pressGoogle Scholar

35.Talairach, J, Tournoux, P. Co-Planar Stereotaxic Atlas of the Human Brain. Stuttgart, Germany: Thieme; 1988.Google Scholar

36.Blumberg, HP, Stern, E, Martinez, D, et al.Increased anterior cingulate and caudate activity in bipolar mania. Biol Psychiatry. 2000;48:1045–1052.CrossRefGoogle ScholarPubMed

37.Ketter, TA, Kimbrell, TA, George, MS, et al.Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder. Biol Psychiatry. 2001;49:97–109.CrossRefGoogle ScholarPubMed

38.Drevets, WC, Bogers, W, Raichle, ME. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur Neuropsychopharmacol. 2002;12:527–544.CrossRefGoogle ScholarPubMed

39.Krüger, S, Seminowicz, D, Goldapple, K, et al.State and trait influences on mood regulation in bipolar disorder: blood flow differences with an acute mood challenge. Biol Psychiatry. 2003;54:1274–1283.CrossRefGoogle ScholarPubMed

40.Lennox, BR, Jacob, R, Calder, AJ, Lupson, V, Bullmore, ET. Behavioural and neurocognitive responses to sad facial affect are attenuated in patients with mania. Psychol Med. 2004;34:795–802.CrossRefGoogle ScholarPubMed

41.Bauer, M, London, ED, Rasgon, N, et al.Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression. Mol Psychiatry. 2005;10:456–469.CrossRefGoogle ScholarPubMed

42.McDonald, C, Bullmore, ET, Sham, PC, et al.Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry. 2004;61:974–984.CrossRefGoogle ScholarPubMed

43.Rich, BA, Vinton, DT, Roberson-Nay, R, et al.Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder. Proc Natl Acad Sci USA. 2006;103:8900–8905.CrossRefGoogle ScholarPubMed

44.Haldane, M, Jogia, J, Cobb, A, Kozuch, E, Kumari, V, Frangou, S. Changes in brain activation during working memory and facial recognition tasks in patients with bipolar disorder with Lamotrigine monotherapy. Eur Neuropsychopharmacol. 2008;18:48–54.CrossRefGoogle ScholarPubMed

45.Mah, L, Zarate, CA Jr, Singh, J, et al.Regional cerebral glucose metabolic abnormalities in bipolar II depression. Biol Psychiatry. 2007;61:765–775.CrossRefGoogle ScholarPubMed

46.Moore, G, Cortese, B, Glitz, D, et al.Lithium increases gray matter in the prefrontal and subgenual prefrontal cortices in treatment responsive bipolar patients. J Clin Psychiatry. In press.Google Scholar

47.Bearden, CE, Thompson, PM, Dalwani, M, et al.Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biol Psychiatry. 2007;62:7–16.CrossRefGoogle ScholarPubMed

48.Shah, PJ, Ebmeier, KR, Glabus, MF, Goodwin, GM. Cortical grey matter reductions associated with treatment-resistant chronic unipolar depression. Controlled magnetic resonance imaging study. Br J Psychiatry. 1998;172:527–532.CrossRefGoogle ScholarPubMed

49.Bremner, JD, Vythilingam, M, Vermetten, E. Reduced volume of orbitofrontal cortex in major depression. Biol Psychiatry. 2002;51:273–279.CrossRefGoogle ScholarPubMed

50.Caetano, SC, Kaur, S, Brambilla, P. Smaller cingulate volumes in unipolar depressed patients. Biol Psychiatry. 2006;59:702–706.CrossRefGoogle ScholarPubMed

51.Tang, Y, Wang, F, Xie, G, et al.Reduced ventral anterior cingulate and amygdala volumes in medication-naïve females with major depressive disorder: a voxel-based morphometric magnetic resonance imaging study. Psychiatry Res. 2007;156:83–86.CrossRefGoogle ScholarPubMed

52.Moore, GJ, Bebchuk, JM, Wilds, IB, Chen, G, Manji, HK. Lithium-induced increase in human brain grey matter. Lancet. 2000;356:1241–1242.CrossRefGoogle ScholarPubMed

53.Brambilla, P, Nicoletti, MA, Harenski, K, et al.Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar subjects. Neuropsychopharmacology. 2002;27:792–779.CrossRefGoogle ScholarPubMed

54.Sharma, V, Menon, R, Carr, TJ, Densmore, M, Mazmanian, D, Williamson, PC. An MRI study of subgenual prefrontal cortex in patients with familial and non-familial bipolar I disorder. J Affect Disord. 2003;77:167–171.CrossRefGoogle ScholarPubMed

55.Bruno, SD, Barker, GJ, Cercignani, M, Symms, M, Ron, MA. A study of bipolar disorder using magnetization transfer imaging and voxel-based morphometry. Brain. 2004;127:2433–2440.CrossRefGoogle ScholarPubMed

56.Doris, A, Belton, E, Ebmeier, KP, Glabus, MF, Marshall, I. Reduction of cingulate gray matter density in poor outcome bipolar illness. Psychiatry Res. 2004;130:153–159.CrossRefGoogle ScholarPubMed

57.Lochhead, RA, Parsey, RV, Oquendo, MA, Mann, JJ. Regional brain gray matter volume differences in patients with bipolar disorder as assessed by optimized voxel-based morphometry. Biol Psychiatry. 2004;55:1154–1162.CrossRefGoogle ScholarPubMed

58.Kaur, S, Sassi, RB, Axelson, D, et al.Cingulate cortex anatomical abnormalities in children and adolescents with bipolar disorder. Am J Psychiatry. 2005;162:1637–1643.CrossRefGoogle ScholarPubMed

59.Sanches, M, Sassi, RB, Axelson, D, et al.Subgenual prefrontal cortex of child and adolescent bipolar patients: a morphometric magnetic resonance imaging study. Psychiatry Res. 2005;138:43–49.CrossRefGoogle ScholarPubMed

60.Zimmerman, ME, DelBello, MP, Getz, GE, Shear, PK, Strakowski, SM. Anterior cingulate subregion volumes and executive function in bipolar disorder. Bipolar Disord. 2006;8:281–288.CrossRefGoogle ScholarPubMed

61.Chiu, S, Widjaja, F, Bates, ME, et al.Anterior cingulate volume in pediatric bipolar disorder and autism. J Affect Disord. 2007;105:93–99.CrossRefGoogle ScholarPubMed

62.Nugent, AC, Milham, MP, Bain, EE, et al.Cortical abnormalities in bipolar disorder investigated with MRI and voxel-based morphometry. Neuroimage. 2006;30:485–497.CrossRefGoogle ScholarPubMed

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

64.Cotter, D, Mackay, D, Landau, S, Kerwin, R, Everall, I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry. 2001;58:545–553.CrossRefGoogle ScholarPubMed

65.Rajkowska, G, Miguel-Hidalgo, JJ, Wei, J, et al.Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999;45:1085–1098.CrossRefGoogle ScholarPubMed

66.Cotter, D, Mackay, D, Chana, G, Beasley, C, Landau, S, Everall, IP. Reduced neuronal size and glial cell density in area 9 of the dorsolateral prefrontal cortex in subjects with major depressive disorder. Cereb Cortex. 2002;12:386–394.CrossRefGoogle ScholarPubMed

67.Uranova, NA, Vostrikov, VM, Orlovskaya, DD, Rachmanova, VI. Oligodendroglial density in the prefrontal cortex in schizophrenia and mood disorders: a study from the Stanley Neuropathology Consortium. Schizophr Res. 2004;67:269–275.CrossRefGoogle ScholarPubMed

68.Bowley, MP, Drevets, WC, Ongür, D, Price, JL. Low glial numbers in the amygdala in major depressive disorder. Biol Psychiatry. 2002;52:404–412.CrossRefGoogle ScholarPubMed

69.Hamidi, M, Drevets, WC, Price, JL. Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol Psychiatry. 2004;55:563–569.CrossRefGoogle ScholarPubMed

70.George, MS, Ketter, TA, Parekh, PI, Horwitz, B, Herscovitch, P, Post, RM. Brain activity during transient sadness and happiness in healthy women. Am J Psychiatry. 1995;152:341–351..Google ScholarPubMed

71.Mayberg, HS, Liotti, M, Brannan, SK, et al.Reciprocal limbic-cortical function and negative mood: converging PET findings in depression and normal sadness. Am J Psychiatry. 1999;156:675–682.CrossRefGoogle ScholarPubMed

72.Rauch, SL, Drevets, WC. Neuroimaging and the neuroanatomy of stress-induced and fear circuitry disorders: the agenda for future research. In: Andrews, G, Charney, DS, Sirovatka, PJ, Regier, DA, eds. Stress-Induced and Fear Circuitry Disorders: Refining the Research Agenda for DSM-V. Washington, DC: American Psychiatric Association; 2008;235–278.Google Scholar

73.Elliott, R, Rubinsztein, JS, Sahakian, BJ, Dolan, RJ. Selective attention to emotional stimuli in a verbal go/no-go task: an fMRI study. Neuroreport. 2000;11:1739–1744.CrossRefGoogle Scholar

74.Gillath, O, Bunge, SA, Shaver, PR, Wendelken, C, Mikulincer, M. Attachment-style differences in the ability to suppress negative thoughts: exploring the neural correlates. Neuroimage. 2005;28:835–847.CrossRefGoogle ScholarPubMed

75.Phelps, EA, Delgado, MR, Nearing, KI, LeDoux, JE. Extinction learning in humans: role of the amygdala and vmPFC. Neuron. 2004;43:897–905.CrossRefGoogle ScholarPubMed

76.Drevets, WC, Ongür, D, Price, JL. Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Mol Psychiatry. 1998;3:220–226, 190–191.CrossRefGoogle ScholarPubMed

77.Bush, G, Luu, P, Posner, MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn Sci. 2000;4:215–222.CrossRefGoogle ScholarPubMed

78.Critchley, HD, Mathias, CJ, Josephs, O, et al.Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence. Brain. 2003;126(pt 10):2139–252.CrossRefGoogle ScholarPubMed

79.Osuch, EA, Ketter, TA, Kimbrell, TA, et al.Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients. Biol Psychiatry. 2000;48:1020–1023.CrossRefGoogle ScholarPubMed

80.Mayberg, HS, Brannan, SK, Mahurin, RK, et al.Cingulate function in depression: a potential predictor of treatment response. Neuroreport. 1997;8:1057–1061.CrossRefGoogle ScholarPubMed

81.Kumano, H, Ida, I, Oshima, A, Takahashi, K, Yuuki, N, et al.Brain metabolic changes associated with predispotion to onset of major depressive disorder and adjustment disorder in cancer patient-a preliminary PET study. J Psychiatr Res. 2007;41:591–599.CrossRefGoogle Scholar

82.Inagaki, M, Yoshikawa, E, Kobayakawa, M, et al.Regional cerebral glucose metabolism in patients with secondary depressive episodes after fatal pancreatic cancer diagnosis. J Affect Disord. 2007;99:231–236.CrossRefGoogle ScholarPubMed

83.Drevets, WC, Price, JL. Neuroimaging and neuropathological studies of mood disorders. In: Licinio, J, Wong, M-L, eds. Biology Of Depression: From Novel Insights To Therapeutic Strategies. Weinheim, Germany: Wiley-Vch Verlag Gmbh & Co; 2005:427–466.CrossRefGoogle Scholar

84.Neumeister, A, Nugent, AC, Waldeck, T, et al.Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch Gen Psychiatry. 2004;61:765–773.CrossRefGoogle ScholarPubMed

85.Hasler, G, Fromm, S, Carlson, PJ, 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.CrossRefGoogle ScholarPubMed

86.Nobler, MS, Oquendo, MA, Kegeles, LS, et al.Decreased regional brain metabolism after ect. Am J Psychiatry. 2001;158:305–308.CrossRefGoogle ScholarPubMed

88.Banasr, M, Duman, RS. Regulation of neurogenesis and gliogenesis by stress and antidepressant treatment. Cns Neurol Disord Drug Targets. 2007;6:311–320.CrossRefGoogle ScholarPubMed

89.Czéh, B, Simon, M, Schmelting, B, Hiemke, C, Fuchs, E. Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology. 2005;31:1616–1626.CrossRefGoogle ScholarPubMed

90.McEwen, BS, Magarinos, AM. Stress and hippocampal plasticity: implications for the pathophysiology of affective disorders. Hum Psychopharmacol. 2001;16(S1):S7–S19.CrossRefGoogle ScholarPubMed

91.Wellman, CL. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J Neurobiol. 2001;49:245–253.CrossRefGoogle ScholarPubMed

92.Radley, JJ, Rocher, AB, Rodriguez, A, et al.Repeated stress alters dendritic spine morphology in the rat medial prefrontal cortex. J Comp Neurol. 2008;507:1141–1150.CrossRefGoogle ScholarPubMed

93.Drevets, WC, Furey, ML. Emotional disorders: depression and the brain. In: Squire, L, ed. The New Encyclopedia of Neuroscience. 4th ed. New York, NY: Elsevier Publishing, Inc; In press.Google Scholar

94.Drevets, WC, Price, JL, Bardgett, ME, Reich, T, Todd, RD, Raichle, ME. Glucose metabolism in the amygdala in depression: relationship to diagnostic subtype and plasma Cortisol levels. Pharmacol Biochem Behav. 2002:71:431–447.CrossRefGoogle ScholarPubMed

95.Shulman, RG, Rothman, DL, Behar, KL, Hyder, F. Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci. 2004;27:489–495.CrossRefGoogle ScholarPubMed

96.Diorio, D, Viau, V, Meaney, MJ. The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. J Neurosci. 1993;13:3839–3847.CrossRefGoogle ScholarPubMed

97.Pezawas, L, Meyer-Lindenberg, A, Drabant, EM, et al.5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci. 2005;8:828–834.CrossRefGoogle ScholarPubMed

98.Caspi, A, Sugden, K, Moffitt, TE, et al.Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science. 2003:301:386–389.CrossRefGoogle ScholarPubMed

99.Stockmeier, CA, Mahajan, GJ, Konick, LC, et al.Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry. 2004;56:640–650.CrossRefGoogle ScholarPubMed

100.Eastwood, SL, Harrison, PJ. Hippocampal synaptic pathology in schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs. Mol Psychiatry. 2000;5:425–432.CrossRefGoogle ScholarPubMed

101.Rosoklija, G, Toomayan, G, Ellis, SP, et al.Structural abnormalities of subicular dendrites in subjects with schizophrenia and mood disorders: preliminary findings. Arch Gen Psychiatry. 2000:57:349–356.CrossRefGoogle ScholarPubMed

102.Drevets, WC, Wymore, AC, Bain, E, et al.Neuromorphometric MRI assessments of the hippocampal subiculum in mood disorders. Biol Psychiatry. 2003;53:189S.Google Scholar

103.Baumann, B, Danos, P, Krell, D, et al.Reduced volume of limbic system-affiliated basal ganglia in mood disorders: preliminary data from a postmortem study. J Neuropsychiatry Clin Neurosci. 1999;11:71–78.CrossRefGoogle ScholarPubMed

104.Morgan, MA, LeDoux, JE. Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats. Behav Neurosci. 1995;109:681–688.CrossRefGoogle Scholar

105.Frysztak, RJ, Neafsey, EJ. The effect of medial frontal cortex lesions on cardiovascular conditioned emotional responses in the rat. Brain Res. 1994;643:181–193.CrossRefGoogle ScholarPubMed

106.Sullivan, RM, Gratton, A. Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats. J Neurosci. 1999;19:2834–2840.CrossRefGoogle ScholarPubMed

107.Carney, RM, Freedland, KE, Veith, RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med. 2005;67(suppl 1):S29–S33.CrossRefGoogle ScholarPubMed

108.Ongür, D, Price, JL. The organization of networks within the orbital and medial prefrontal cortex of rats, monkeys and humans. Cereb Cortex. 2000;10:206–219.CrossRefGoogle ScholarPubMed

109.Bechara, A, Damasio, AR, Damasio, H, Anderson, SW. Insensitivity to future consequences following damage to human prefrontal cortex. Cognition. 1994;50:7–15.CrossRefGoogle ScholarPubMed

110.Damasio, AR. Descarte's Error: Emotion, Reason, and the Human Brain. New York, NY: G.P. Putnam's Sons; 1995.Google Scholar