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Meta-analysis of volumetric abnormalities in cortico-striatal-pallidal-thalamic circuits in major depressive disorder

  • E. Bora (a1), B. J. Harrison (a1), C. G. Davey (a1) (a2), M. Yücel (a1) (a2) and C. Pantelis (a1)...



Abnormalities in cortico-striatal-pallidal-thalamic (CSPT) circuits have been implicated in major depressive disorder (MDD). However, the robustness of these findings across studies is unclear, as is the extent to which they are influenced by demographic, clinical and pharmacological factors.


With the aim of clarifying these questions, we conducted a meta-analysis to map the volumetric abnormalities that were most robustly identified in CSPT circuits of individuals with MDD. A systematic search identified 41 studies meeting our inclusion criteria.


There were significant volume reductions in prefrontal (especially orbitofrontal) and anterior cingulate cortices, and also in subcortical structures such as the caudate nucleus and putamen, with effect sizes ranging from small to moderate. The subgenual anterior cingulate and orbitofrontal cortices were significantly smaller in antidepressant-free samples compared to medicated patients. Late-life depression (LLD) tended to be associated with smaller volumes in circumscribed frontal and subcortical structures, with the most robust differences being found in thalamic volume.


Individuals with major depression demonstrate volumetric abnormalities of CSPT circuits. However, these observations may be restricted to certain subgroups, highlighting the clinical heterogeneity of the disorder. On the basis of this meta-analysis, CSPT abnormalities were more prominent in those with LLD whereas antidepressant use seemed to normalize certain cortical volumetric abnormalities.


Corresponding author

*Address for correspondence: Dr E. Bora, Alan Gilbert Building NNF level 3, Carlton 3053, Australia. (Email:


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Alexander, GE, Crutcher, MD, DeLong, MR (1990). Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, ‘prefrontal’ and ‘limbic’ functions. Progress in Brain Research 85, 119146.
Alexander, GE, DeLong, MR, Strick, PL (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience 9, 357381.
Almeida, OP, Burton, EJ, Ferrier, N, McKeith, IG, O'Brien, JT (2003). Depression with late onset is associated with right frontal lobe atrophy. Psychological Medicine 3, 675681.
Andreescu, C, Butters, MA, Begley, A, Rajji, T, Wu, M, Meltzer, CC, Reynolds, CF 3rd, Aizenstein, H (2008). Gray matter changes in late life depression – a structural MRI analysis. Neuropsychopharmacology 33, 25662572.
Ballmaier, M, Toga, AW, Blanton, RE, Sowell, ER, Lavretsky, H, Peterson, J, Pham, D, Kumar, A (2004). Anterior cingulate, gyrus rectus, and orbitofrontal abnormalities in elderly depressed patients: an MRI-based parcellation of the prefrontal cortex. American Journal of Psychiatry 161, 99–108.
Bax, L, Yu, LM, Ikeda, N, Tsuruta, H, Moons, KGM (2006). Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Medical Research Methodology 6, 50.
Bilgi, MM, Ozalay, O, Cağdaş Eker, M, Kitiş, O, Ozan, E, Eker, O, Simş, F, Işman Haznedaroğlu, D, Gönül, AS (2010). Small frontal gray matter volume in first-episode depression patients [in Turkish]. Türk Psikiyatri Dergisi 21, 185194.
Bora, E, Fornito, A, Pantelis, C, Yucel, M (2011). Gray matter abnormalities in major depressive disorder: a meta-analysis of voxel based morphometry studies. Journal of Affective Disorders. Published online: 19 April 2011. doi: 10.1016/j.jad.2011.03.049.
Botteron, KN, Raichle, ME, Drevets, WC, Heath, AC, Todd, RD (2002). Volumetric reduction in left subgenual prefrontal cortex in early onset depression. Biological Psychiatry 51, 342344.
Brambilla, P, Nicoletti, MA, Harenski, K, Sassi, RB, Mallinger, AG, Frank, E, Kupfer, DJ, Keshavan, MS, Soares, JC (2002). Anatomical MRI study of subgenual prefrontal cortex in bipolar and unipolar subjects. Neuropsychopharmacology 27, 792799.
Bremner, JD, Narayan, M, Anderson, ER, Staib, LH, Miller, HL, Charney, DS (2000). Hippocampal volume reduction in major depression. American Journal of Psychiatry 157, 115118.
Bremner, JD, Vythilingam, M, Vermetten, E, Nazeer, A, Adil, J, Khan, S, Staib, LH, Charney, DS (2002). Reduced volume of orbitofrontal cortex in major depression. Biological Psychiatry 51, 273279.
Bush, G, Luu, P, Posner, MI (2000). Cognitive and emotional influences in anterior cingulate cortex. Trends in Cognitive Science 4, 215222.
Caetano, SC, Kaur, S, Brambilla, P, Nicoletti, M, Hatch, JP, Sassi, RB, Mallinger, AG, Keshavan, MS, Kupfer, DJ, Frank, E, Soares, JC (2006). Smaller cingulate volumes in unipolar depressed patients. Biological Psychiatry 59, 702706.
Caetano, SC, Sassi, R, Brambilla, P, Harenski, K, Nicoletti, M, Mallinger, AG, Frank, E, Kupfer, DJ, Keshavan, MS, Soares, JC (2001). MRI study of thalamic volumes in bipolar and unipolar patients and healthy individuals. Psychiatry Research 108, 161168.
Campbell, S, Marriott, M, Nahmias, C, MacQueen, GM (2004). Lower hippocampal volume in patients suffering from depression: a meta-analysis. American Journal of Psychiatry 161, 598607.
Castrén, E, Võikar, V, Rantamäki, T (2007). Role of neurotrophic factors in depression. Current Opinion in Pharmacology 7, 1821.
Chen, HH, Rosenberg, DR, MacMaster, FP, Easter, PC, Caetano, SC, Nicoletti, M, Hatch, JP, Nery, FG, Soares, JC (2008). Orbitofrontal cortex volumes in medication naïve children with major depressive disorder: a magnetic resonance imaging study. Journal of Child and Adolescent Psychopharmacology 18, 551556.
Coryell, W, Nopoulos, P, Drevets, W, Wilson, T, Andreasen, NC (2005). Subgenual prefrontal cortex volumes in major depressive disorder and schizophrenia: diagnostic specificity and prognostic implications. American Journal of Psychiatry 162, 17061712.
Delaloye, C, Moy, G, de Bilbao, F, Baudois, S, Weber, K, Hofer, F, Ragno Paquier, C, Donati, A, Canuto, A, Giardini, U, von Gunten, A, Stancu, RI, Lazeyras, F, Millet, P, Scheltens, P, Giannakopoulos, P, Gold, G (2010). Neuroanatomical and neuropsychological features of elderly euthymic depressed patients with early- and late-onset. Journal of Neurological Science 299, 1923.
Drevets, WC, Ongür, D, Price, JL (1998). Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders. Molecular Psychiatry 3, 220226.
Drevets, WC, Price, JL, Furey, ML (2008). Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Structure and Function 213, 93–118.
Dupont, RM, Jernigan, TL, Heindel, W, Butters, N, Shafer, K, Wilson, T, Hesselink, J, Gillin, JC (1995). Magnetic resonance imaging and mood disorders. Localization of white matter and other subcortical abnormalities. Archives of General Psychiatry 52, 747755.
Elderkin-Thompson, V, Hellemann, G, Pham, D, Kumar, A (2009). Prefrontal brain morphology and executive function in healthy and depressed elderly. International Journal of Geriatric Psychiatry 24, 459468.
Fitzgerald, PB, Laird, AR, Maller, J, Daskalakis, ZJ (2008). A meta-analytic study of changes in brain activation in depression. Human Brain Mapping 29, 683695.
Frodl, T, Jäger, M, Born, C, Ritter, S, Kraft, E, Zetzsche, T, Bottlender, R, Leinsinger, G, Reiser, M, Möller, HJ, Meisenzahl, E (2008). Anterior cingulate cortex does not differ between patients with major depression and healthy controls, but relatively large anterior cingulate cortex predicts a good clinical course. Psychiatry Research 163, 7683.
Frodl, T, Schaub, A, Banac, S, Charypar, M, Jäger, M, Kümmler, P, Bottlender, R, Zetzsche, T, Born, C, Leinsinger, G, Reiser, M, Möller, HJ, Meisenzahl, EM (2006). Reduced hippocampal volume correlates with executive dysfunctioning in major depression. Journal of Psychiatry and Neuroscience 31, 316323.
Haber, SN, Calzavara, R (2009). The cortico-basal ganglia integrative network: the role of the thalamus. Brain Research Bulletin 78, 6974.
Hajek, T, Kozeny, J, Kopecek, M, Alda, M, Höschl, C (2008). Reduced subgenual cingulate volumes in mood disorders: a meta-analysis. Journal of Psychiatry and Neuroscience 33, 9199.
Hamilton, JP, Siemer, M, Gotlib, IH (2008). Amygdala volume in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Molecular Psychiatry 13, 993–1000.
Hannestad, J, Taylor, WD, McQuoid, DR, Payne, ME, Krishnan, KR, Steffens, DC, Macfall, JR (2006). White matter lesion volumes and caudate volumes in late-life depression. International Journal of Geriatric Psychiatry 21, 11931198.
Hastings, RS, Parsey, RV, Oquendo, MA, Arango, V, Mann, JJ (2004). Volumetric analysis of the prefrontal cortex, amygdala, and hippocampus in major depression. Neuropsychopharmacology 29, 952959.
Herrmann, LL, Goodwin, GM, Ebmeier, KP (2007). The cognitive neuropsychology of depression in the elderly. Psychological Medicine 37, 16931702.
Herrmann, LL, Le Masurier, M, Ebmeier, KP (2008). White matter hyperintensities in late life depression: a systematic review. Journal of Neurology, Neurosurgery, and Psychiatry 79, 619624.
Hickie, IB, Naismith, SL, Ward, PB, Little, CL, Pearson, M, Scott, EM, Mitchell, P, Wilhelm, K, Parker, G (2007). Psychomotor slowing in older patients with major depression: relationships with blood flow in the caudate nucleus and white matter lesions. Psychiatry Reserach 155, 211220.
Higgins, JPT, Thompson, SG (2002). Quantifying heterogeneity in a meta-analysis. Statistical Medicine 21, 15391558.
Holland, PC, Gallagher, M (2004). Amygdala-frontal interactions and reward expectancy. Current Opinion in Neurobiology 14, 148155.
Husain, MM, McDonald, WM, Doraiswamy, PM, Figiel, GS, Na, C, Escalona, PR, Boyko, OB, Nemeroff, CB, Krishnan, KR (1991). A magnetic resonance imaging study of putamen nuclei in major depression. Psychiatry Research 40, 9599.
Janssen, J, Hulshoff Pol, HE, Lampe, IK, Schnack, HG, de Leeuw, FE, Kahn, RS, Heeren, TJ (2004). Hippocampal changes and white matter lesions in early onset depression. Biological Psychiatry 56, 825831.
Koolschijn, PC, van Haren, NE, Lensvelt-Mulders, GJ, Hulshoff Pol, HE, Kahn, RS (2009). Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Human Brain Mapping 30, 37193735.
Krishnan, KR, McDonald, WM, Doraiswamy, PM, Tupler, LA, Husain, M, Boyko, OB, Figiel, GS, Ellinwood, EH Jr. (1993). Neuroanatomical substrates of depression in the elderly. European Archives of Psychiatry and Clinical Neuroscience 243, 4146.
Krishnan, KR, McDonald, WM, Escalona, PR, Doraiswamy, PM, Na, C, Husain, MM, Figiel, GS, Boyko, OB, Ellinwood, EH, Nemeroff, CB (1992). Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations. Archives of General Psychiatry 49, 553557.
Kumar, A, Jin, Z, Bilker, W, Udupa, J, Gottlieb, G (1998). Late-onset minor and major depression: early evidence for common neuroanatomical substrates detected by using MRI. Proceedings of the National Academy of Sciences USA 95, 76547658.
Lacerda, AL, Keshavan, MS, Hardan, AY, Yorbik, O, Brambilla, P, Sassi, RB, Nicoletti, M, Mallinger, AG, Frank, E, Kupfer, DJ, Soares, JC (2004). Anatomic evaluation of the orbitofrontal cortex in major depressive disorder. Biological Psychiatry 55, 353358.
Lacerda, AL, Nicoletti, MA, Brambilla, P, Sassi, RB, Mallinger, AG, Frank, E, Kupfer, DJ, Keshavan, MS, Soares, JC (2003). Anatomical MRI study of basal ganglia in major depressive disorder. Psychiatry Research 124, 129140.
Lauterbach, EC, Cummings, JL, Duffy, J, Coffey, CE, Kaufer, D, Lovell, M, Malloy, P, Reeve, A, Royall, DR, Rummans, TA, Salloway, SP (1998). Neuropsychiatric correlates and treatment of lenticulostriatal diseases: a review of the literature and overview of research opportunities in Huntington's, Wilson's, and Fahr's diseases. A report of the ANPA Committee on Research. American Neuropsychiatric Association. Journal of Neuropsychiatry and Clinical Neurosciences 10, 249266.
Lavretsky, H, Roybal, DJ, Ballmaier, M, Toga, AW, Kumar, A (2005). Antidepressant exposure may protect against decrement in frontal gray matter volumes in geriatric depression. Journal of Clinical Psychiatry 66, 964967.
Lenze, EJ, Sheline, YI (1999). Absence of striatal volume differences between depressed subjects with no comorbid medical illness and matched comparison subjects. American Journal of Psychiatry 156, 19891991.
Marchand, WR (2010). Cortico-basal ganglia circuitry: a review of key research and implications for functional connectivity studies of mood and anxiety disorders. Brain Structure and Function 215, 7396.
Marchand, WR, Yurgelun-Todd, D (2010). Striatal structure and function in mood disorders: a comprehensive review. Bipolar Disorders 12, 764785.
Matsuo, K, Rosenberg, DR, Easter, PC, MacMaster, FP, Chen, HH, Nicoletti, M, Caetano, SC, Hatch, JP, Soares, JC (2008). Striatal volume abnormalities in treatment-naïve patients diagnosed with pediatric major depressive disorder. Journal of Child and Adolescent Psychopharmacology 18, 121131.
Mayberg, HS (1997). Limbic-cortical dysregulation: a proposed model of depression. Journal of Neuropsychiatry and Clinical Neurosciences 9, 471481.
Moher, D, Liberati, A, Tetzlaff, J, Altman, DG; PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339, b2535.
Monkul, ES, Hatch, JP, Nicoletti, MA, Spence, S, Brambilla, P, Lacerda, AL, Sassi, RB, Mallinger, AG, Keshavan, MS, Soares, JC (2007). Fronto-limbic brain structures in suicidal and non-suicidal female patients with major depressive disorder. Molecular Psychiatry 12, 360366.
Pan, CC, McQuoid, DR, Taylor, WD, Payne, ME, Ashley-Koch, A, Steffens, DC (2009). Association analysis of the COMT/MTHFR genes and geriatric depression: an MRI study of the putamen. International Journal of Geriatric Psychiatry 24, 847855.
Pantel, J, Schröder, J, Essig, M, Popp, D, Dech, H, Knopp, MV, Schad, LR, Eysenbach, K, Backenstrass, M, Friedlinger, M (1997). Quantitative magnetic resonance imaging in geriatric depression and primary degenerative dementia. Journal of Affective Disorders 42, 6983.
Parashos, IA, Tupler, LA, Blitchington, T, Krishnan, KR (1998). Magnetic-resonance morphometry in patients with major depression. Psychiatry Research 84, 7–15.
Parker, G (2000). Classifying depression: should paradigms lost be regained? American Journal of Psychiatry 157, 11951203.
Pillay, SS, Renshaw, PF, Bonello, CM, Lafer, BC, Fava, M, Yurgelun-Todd, DA (1998). Quantitative magnetic resonance imaging study of caudate and lenticular nucleus gray matter volume in primary unipolar major depression: relationship to treatment response and clinical severity. Psychiatry Research 84, 6174.
Pizzagalli, DA (2011). Frontocingulate dysfunction in depression: toward biomarkers of treatment response. Neuropsychopharmacology 36, 183206.
Rajkowska, G, Miguel-Hidalgo, JJ, Wei, J (1999). Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biological Psychiatry 45, 10851098.
Rogers, MA, Bradshaw, JL, Pantelis, C, Phillips, JG (1998). Frontostriatal deficits in unipolar major depression. Brain Research Bulletin 47, 297310.
Rolls, ET (2000). The orbitofrontal cortex and reward. Cerebral Cortex 10, 284294.
Salokangas, RK, Cannon, T, Van Erp, T, Ilonen, T, Taiminen, T, Karlsson, H, Lauerma, H, Leinonen, KM, Wallenius, E, Kaljonen, A, Syvälahti, E, Vilkman, H, Alanen, A, Hietala, J (2002). Structural magnetic resonance imaging in patients with first-episode schizophrenia, psychotic and severe non-psychotic depression and healthy controls. Results of the schizophrenia and affective psychoses (SAP) project. British Journal of Psychiatry. Supplement 43, s58s65.
Schweitzer, I, Tuckwell, V, Ames, D, O'Brien, J (2001). Structural neuroimaging studies in late-life depression: a review. World Journal of Biological Psychiatry 2, 8388.
Steingard, RJ, Renshaw, PF, Hennen, J, Lenox, M, Cintron, CB, Young, AD, Connor, DF, Au, TH, Yurgelun-Todd, DA (2002). Smaller frontal lobe white matter volumes in depressed adolescents. Biological Psychiatry 52, 413417.
Taylor, WD, Macfall, JR, Payne, ME, McQuoid, DR, Steffens, DC, Provenzale, JM, Krishnan, KR (2007). Orbitofrontal cortex volume in late life depression: influence of hyperintense lesions and genetic polymorphisms. Psychological Medicine 37, 17631773.
Walterfang, M, Evans, A, Looi, JC, Jung, HH, Danek, A, Walker, RH, Velakoulis, D (2011). The neuropsychiatry of neuroacanthocytosis syndromes. Neuroscience and Biobehavioral Reviews 35, 12751283.
Weber, K, Giannakopoulos, P, Delaloye, C, de Bilbao, F, Moy, G, Moussa, A, Rubio, MM, Ebbing, K, Meuli, R, Lazeyras, F, Meiler-Mititelu, C, Herrmann, FR, Gold, G, Canuto, A (2010). Volumetric MRI changes, cognition and personality traits in old age depression. Journal of Affective Disorders 124, 275282.
Yucel, K, McKinnon, M, Chahal, R, Taylor, V, Macdonald, K, Joffe, R, MacQueen, G (2009). Increased subgenual prefrontal cortex size in remitted patients with major depressive disorder. Psychiatry Research 173, 7176.
Yucel, K, McKinnon, MC, Chahal, R, Taylor, VH, Macdonald, K, Joffe, R, MacQueen, GM (2008). Anterior cingulate volumes in never-treated patients with major depressive disorder. Neuropsychopharmacology 33, 31573163.
Yücel, M, Wood, SJ, Fornito, A, Riffkin, J, Velakoulis, D, Pantelis, C (2003). Anterior cingulate dysfunction: implications for psychiatric disorders. Journal of Psychiatry and Neuroscience 8, 350354.


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Fig. S1. Flow diagram for meta-analysis of volumetric studies of CSPT in MDD

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Meta-analysis of volumetric abnormalities in cortico-striatal-pallidal-thalamic circuits in major depressive disorder

  • E. Bora (a1), B. J. Harrison (a1), C. G. Davey (a1) (a2), M. Yücel (a1) (a2) and C. Pantelis (a1)...


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