Skip to main content Accessibility help

Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties

  • R. Admon (a1), L. D. Nickerson (a2), D. G. Dillon (a1), A. J. Holmes (a3) (a4), R. Bogdan (a5), P. Kumar (a1), D. D. Dougherty (a4), D. V. Iosifescu (a6), D. Mischoulon (a4), M. Fava (a4) and D. A. Pizzagalli (a1) (a2)...



Individuals with major depressive disorder (MDD) are characterized by maladaptive responses to both positive and negative outcomes, which have been linked to localized abnormal activations in cortical and striatal brain regions. However, the exact neural circuitry implicated in such abnormalities remains largely unexplored.


In this study 26 unmedicated adults with MDD and 29 matched healthy controls (HCs) completed a monetary incentive delay task during functional magnetic resonance imaging (fMRI). Psychophysiological interaction (PPI) analyses probed group differences in connectivity separately in response to positive and negative outcomes (i.e. monetary gains and penalties).


Relative to HCs, MDD subjects displayed decreased connectivity between the caudate and dorsal anterior cingulate cortex (dACC) in response to monetary gains, yet increased connectivity between the caudate and a different, more rostral, dACC subregion in response to monetary penalties. Moreover, exploratory analyses of 14 MDD patients who completed a 12-week, double-blind, placebo-controlled clinical trial after the baseline fMRI scans indicated that a more normative pattern of cortico-striatal connectivity pre-treatment was associated with greater improvement in symptoms 12 weeks later.


These results identify the caudate as a region with dissociable incentive-dependent dACC connectivity abnormalities in MDD, and provide initial evidence that cortico-striatal circuitry may play a role in MDD treatment response. Given the role of cortico-striatal circuitry in encoding action–outcome contingencies, such dysregulated connectivity may relate to the prominent disruptions in goal-directed behavior that characterize MDD.


Corresponding author

* Address for correspondence: D. A. Pizzagalli, Ph.D., Center for Depression, Anxiety and Stress Research, Room 233C, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA. (Email:


Hide All
Alloy, LB, Abramson, LY (1979). Judgment of contingency in depressed and nondepressed students: sadder but wiser? Journal of Experimental Psychology . General 108, 441485.
Baliki, MN, Mansour, A, Baria, AT, Huang, L, Berger, SE, Fields, HL, Apkarian, AV (2013). Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain. Journal of Neuroscience 33, 1638316393.
Beats, BC, Sahakian, BJ, Levy, R (1996). Cognitive performance in tests sensitive to frontal lobe dysfunction in the elderly depressed. Psychological Medicine 26, 591603.
Becerra, L, Breiter, HC, Wise, R, Gonzalez, RG, Borsook, D (2001). Reward circuitry activation by noxious thermal stimuli. Neuron 32, 927946.
Beck, AT (2005). The current state of cognitive therapy: a 40-year retrospective. Archives of General Psychiatry 62, 953959.
Blomstedt, P, Sjoberg, RL, Hansson, M, Bodlund, O, Hariz, MI (2011). Deep brain stimulation in the treatment of depression. Acta Psychiatrica Scandinavica 123, 411.
Bress, JN, Foti, D, Kotov, R, Klein, DN, Hajcak, G (2013). Blunted neural response to rewards prospectively predicts depression in adolescent girls. Psychophysiology 50, 7481.
Delgado, MR (2007). Reward-related responses in the human striatum. Annals of the New York Academy of Sciences 1104, 7088.
Delgado, MR, Li, J, Schiller, D, Phelps, EA (2008). The role of the striatum in aversive learning and aversive prediction errors. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 363, 37873800.
Desikan, RS, Segonne, F, Fischl, B, Quinn, BT, Dickerson, BC, Blacker, D, Buckner, RL, Dale, AM, Maguire, RP, Hyman, BT, Albert, MS, Killiany, RJ (2006). An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. NeuroImage 31, 968980.
Elliott, R, Sahakian, BJ, McKay, AP, Herrod, JJ, Robbins, TW, Paykel, ES (1996). Neuropsychological impairments in unipolar depression: the influence of perceived failure on subsequent performance. Psychological Medicine 26, 975989.
First, MB, Spitzer, RL, Gibbon, M, Williams, JBW (2002). Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). New York State Psychiatric Institute, Biometrics Research: New York.
Forbes, EE, Christopher May, J, Siegle, GJ, Ladouceur, CD, Ryan, ND, Carter, CS, Birmaher, B, Axelson, DA, Dahl, RE (2006). Reward-related decision-making in pediatric major depressive disorder: an fMRI study. Journal of Child Psychology and Psychiatry 47, 10311040.
Forbes, EE, Hariri, AR, Martin, SL, Silk, JS, Moyles, DL, Fisher, PM, Brown, SM, Ryan, ND, Birmaher, B, Axelson, DA, Dahl, RE (2009). Altered striatal activation predicting real-world positive affect in adolescent major depressive disorder. American Journal of Psychiatry 166, 6473.
Foti, D, Hajcak, G (2009). Depression and reduced sensitivity to non-rewards versus rewards: evidence from event-related potentials. Biological Psychology 81, 18.
Friston, KJ, Buechel, C, Fink, GR, Morris, J, Rolls, E, Dolan, RJ (1997). Psychophysiological and modulatory interactions in neuroimaging. NeuroImage 6, 218229.
Fu, CH, Steiner, H, Costafreda, SG (2013). Predictive neural biomarkers of clinical response in depression: a meta-analysis of functional and structural neuroimaging studies of pharmacological and psychological therapies. Neurobiology of Disease 52, 7583.
Gehring, WJ, Willoughby, AR (2002). The medial frontal cortex and the rapid processing of monetary gains and losses. Science 295, 22792282.
Haber, SN, Knutson, B (2010). The reward circuit: linking primate anatomy and human imaging. Neuropsychopharmacology 35, 426.
Hamilton, M (1967). Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology 6, 278296.
Heller, AS, Johnstone, T, Light, SN, Peterson, MJ, Kolden, GG, Kalin, NH, Davidson, RJ (2013). Relationships between changes in sustained fronto-striatal connectivity and positive affect in major depression resulting from antidepressant treatment. American Journal of Psychiatry 170, 197206.
Heller, AS, Johnstone, T, Shackman, AJ, Light, SN, Peterson, MJ, Kolden, GG, Kalin, NH, Davidson, RJ (2009). Reduced capacity to sustain positive emotion in major depression reflects diminished maintenance of fronto-striatal brain activation. Proceedings of the National Academy of Sciences USA 106, 2244522450.
Holmes, AJ, Pizzagalli, DA (2008). Spatiotemporal dynamics of error processing dysfunctions in major depressive disorder. Archives of General Psychiatry 65, 179188.
Jenkinson, M, Bannister, P, Brady, M, Smith, S (2002). Improved optimization for the robust and accurate linear registration and motion correction of brain images. NeuroImage 17, 825841.
Knight, EJ, Min, HK, Hwang, SC, Marsh, MP, Paek, S, Kim, I, Felmlee, JP, Abulseoud, OA, Bennet, KE, Frye, MA, Lee, KH (2013). Nucleus accumbens deep brain stimulation results in insula and prefrontal activation: a large animal FMRI study. PLoS One 8, e56640.
Knutson, B, Bhanji, JP, Cooney, RE, Atlas, LY, Gotlib, IH (2008). Neural responses to monetary incentives in major depression. Biological Psychiatry 63, 686692.
Kumar, P, Waiter, G, Ahearn, T, Milders, M, Reid, I, Steele, JD (2008). Abnormal temporal difference reward-learning signals in major depression. Brain 131, 20842093.
Lawrence, NS, Williams, AM, Surguladze, S, Giampietro, V, Brammer, MJ, Andrew, C, Frangou, S, Ecker, C, Phillips, ML (2004). Subcortical and ventral prefrontal cortical neural responses to facial expressions distinguish patients with bipolar disorder and major depression. Biological Psychiatry 55, 578587.
Liu, WH, Chan, RC, Wang, LZ, Huang, J, Cheung, EF, Gong, QY, Gollan, JK (2011). Deficits in sustaining reward responses in subsyndromal and syndromal major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 35, 10451052.
Mattfeld, AT, Gluck, MA, Stark, CE (2011). Functional specialization within the striatum along both the dorsal/ventral and anterior/posterior axes during associative learning via reward and punishment. Learning and Memory 18, 703711.
Mayberg, HS (1997). Limbic-cortical dysregulation: a proposed model of depression. Journal of Neuropsychiatry and Clinical Neurosciences 9, 471481.
McLaren, DG, Ries, ML, Xu, G, Johnson, SC (2012). A generalized form of context-dependent psychophysiological interactions (gPPI): a comparison to standard approaches. NeuroImage 61, 12771286.
Mischoulon, D, Price, LH, Carpenter, LL, Tyrka, AR, Papakostas, GI, Baer, L, Dording, CM, Clain, AJ, Durham, K, Walker, R, Ludington, E, Fava, M (2013). A double-blind, randomized, placebo-controlled clinical trial of S-adenosyl-L-methionine (SAMe) versus escitalopram in major depressive disorder. Journal of Clinical Psychiatry. Published online: 24 December 2013 . doi: 10.4088/JCP.13m08591.
Niznikiewicz, MA, Delgado, MR (2011). Two sides of the same coin: learning via positive and negative reinforcers in the human striatum. Developmental Cognitive Neuroscience 1, 494505.
O'Reilly, JX, Woolrich, MW, Behrens, TE, Smith, SM, Johansen-Berg, H (2012). Tools of the trade: psychophysiological interactions and functional connectivity. Social Cognitive and Affective Neuroscience 7, 604609.
Papakostas, GI (2009). Evidence for S-adenosyl-L-methionine (SAM-e) for the treatment of major depressive disorder. Journal of Clinical Psychiatry 70 (Suppl. 5), 1822.
Papakostas, GI, Alpert, JE, Fava, M (2003). S-adenosyl-methionine in depression: a comprehensive review of the literature. Current Psychiatry Reports 5, 460466.
Papakostas, GI, Mischoulon, D, Shyu, I, Alpert, JE, Fava, M (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. American Journal of Psychiatry 167, 942948.
Phillips, JL, Batten, LA, Aldosary, F, Tremblay, P, Blier, P (2012). Brain-volume increase with sustained remission in patients with treatment-resistant unipolar depression. Journal of Clinical Psychiatry 73, 625631.
Pizzagalli, DA, Holmes, AJ, Dillon, DG, Goetz, EL, Birk, JL, Bogdan, R, Dougherty, DD, Iosifescu, DV, Rauch, SL, Fava, M (2009). Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. American Journal of Psychiatry 166, 702710.
Pizzagalli, DA, Iosifescu, D, Hallett, LA, Ratner, KG, Fava, M (2008). Reduced hedonic capacity in major depressive disorder: evidence from a probabilistic reward task. Journal of Psychiatry Research 43, 7687.
Pizzagalli, DA, Peccoralo, LA, Davidson, RJ, Cohen, JD (2006). Resting anterior cingulate activity and abnormal responses to errors in subjects with elevated depressive symptoms: a 128-channel EEG study. Human Brain Mapping 27, 185201.
Power, JD, Barnes, KA, Snyder, AZ, Schlaggar, BL, Petersen, SE (2012). Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. NeuroImage 59, 21422154.
Rangel, A, Camerer, C, Montague, PR (2008). A framework for studying the neurobiology of value-based decision making. Nature Reviews Neuroscience 9, 545556.
Rottenberg, J, Kasch, KL, Gross, JJ, Gotlib, IH (2002). Sadness and amusement reactivity differentially predict concurrent and prospective functioning in major depressive disorder. Emotion 2, 135146.
Schaefer, HS, Putnam, KM, Benca, RM, Davidson, RJ (2006). Event-related functional magnetic resonance imaging measures of neural activity to positive social stimuli in pre-and post-treatment depression. Biological Psychiatry 60, 974986.
Seligman, ME (1972). Learned helplessness. Annual Review of Medicine 23, 407412.
Seymour, B, Daw, N, Dayan, P, Singer, T, Dolan, R (2007). Differential encoding of losses and gains in the human striatum. Journal of Neuroscience 27, 48264831.
Shenhav, A, Botvinick, MM, Cohen, JD (2013). The expected value of control: an integrative theory of anterior cingulate cortex function. Neuron 79, 217240.
Smith, SM (2002). Fast robust automated brain extraction. Human Brain Mapping 17, 143155.
Smith, SM, Jenkinson, M, Woolrich, MW, Beckmann, CF, Behrens, TE, Johansen-Berg, H, Bannister, PR, De Luca, M, Drobnjak, I, Flitney, DE, Niazy, RK, Saunders, J, Vickers, J, Zhang, Y, De Stefano, N, Brady, JM, Matthews, PM (2004). Advances in functional and structural MR image analysis and implementation as FSL. NeuroImage 23 (Suppl. 1), S208219.
Smoski, MJ, Felder, J, Bizzell, J, Green, SR, Ernst, M, Lynch, TR, Dichter, GS (2009). fMRI of alterations in reward selection, anticipation, and feedback in major depressive disorder. Journal of Affective Disorders 118, 6978.
Steffens, DC, Wagner, HR, Levy, RM, Horn, KA, Krishnan, KR (2001). Performance feedback deficit in geriatric depression. Biological Psychiatry 50, 358363.
Tricomi, EM, Delgado, MR, Fiez, JA (2004). Modulation of caudate activity by action contingency. Neuron 41, 281292.
Vrieze, E, Pizzagalli, DA, Demyttenaere, K, Hompes, T, Sienaert, P, de Boer, P, Schmidt, M, Claes, S (2013). Reduced reward learning predicts outcome in major depressive disorder. Biological Psychiatry 73, 639645.
Wenzlaff, RM, Grozier, SA (1988). Depression and the magnification of failure. Journal of Abnormal Psychology 97, 9093.
Worsley, KJ (2001). Statistical analysis of activation images. In Functional MRI: An Introduction to the Methods (ed. Jezzard, P., Matthews, P. M. and Smith, S. M.), pp. 251270. Oxford University Press: Oxford.
Zhang, A, Ajilore, O, Zhan, L, Gadelkarim, J, Korthauer, L, Yang, S, Leow, A, Kumar, A (2013). White matter tract integrity of anterior limb of internal capsule in major depression and type 2 diabetes. Neuropsychopharmacology 38, 14511459.
Zhu, X, Wang, X, Xiao, J, Zhong, M, Liao, J, Yao, S (2011). Altered white matter integrity in first-episode, treatment-naive young adults with major depressive disorder: a tract-based spatial statistics study. Brain Research 1369, 223229.
Zou, K, Huang, X, Li, T, Gong, Q, Li, Z, Ou-yang, L, Deng, W, Chen, Q, Li, C, Ding, Y, Sun, X (2008). Alterations of white matter integrity in adults with major depressive disorder: a magnetic resonance imaging study. Journal of Psychiatry and Neuroscience 33, 525530.


Type Description Title
Supplementary materials

Admon Supplementary Material
Figure S1

 Unknown (19 KB)
19 KB
Supplementary materials

Admon Supplementary Material
Table S1

 Word (35 KB)
35 KB


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed