Hostname: page-component-cd9895bd7-mkpzs Total loading time: 0 Render date: 2024-12-28T04:12:58.230Z Has data issue: false hasContentIssue false
  • English
  • Français

Altered reward processing in the orbitofrontal cortex and hippocampus in healthy first-degree relatives of patients with depression

Published online by Cambridge University Press:  19 July 2013

J. Macoveanu ,
U. Knorr ,
A. Skimminge ,
M. G. Søndergaard ,
A. Jørgensen ,
M. Fauerholdt-Jepsen ,
O. B. Paulson ,
G. M. Knudsen ,
H. R. Siebner  and
L. V. Kessing
J. Macoveanu*
Affiliation:
Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen University Hospital, Denmark
U. Knorr
Affiliation:
Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark
A. Skimminge
Affiliation:
Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark
M. G. Søndergaard
Affiliation:
Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark
A. Jørgensen
Affiliation:
Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark
M. Fauerholdt-Jepsen
Affiliation:
Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark
O. B. Paulson
Affiliation:
Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen University Hospital, Denmark Neurobiology Research Unit, Rigshospitalet, Copenhagen University Hospital, Denmark
G. M. Knudsen
Affiliation:
Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen University Hospital, Denmark Neurobiology Research Unit, Rigshospitalet, Copenhagen University Hospital, Denmark
H. R. Siebner
Affiliation:
Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Denmark Center for Integrated Molecular Brain Imaging, Rigshospitalet, Copenhagen University Hospital, Denmark
L. V. Kessing
Affiliation:
Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Denmark
*
* Address for correspondence: J. Macoveanu, Ph.D., Danish Research Center for Magnetic Resonance, Hvidovre Hospital, Copenhagen University Hospital, Kettegaard Allé 30, DK-2650 Hvidovre, Denmark. (Email: julianm@drcmr.dk)
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Healthy first-degree relatives of patients with major depression (rMD+) show brain structure and functional response anomalies and have elevated risk for developing depression, a disorder linked to abnormal serotonergic neurotransmission and reward processing.

Method

In a two-step functional magnetic resonance imaging (fMRI) investigation, we first evaluated whether positive and negative monetary outcomes were differentially processed by rMD+ individuals compared to healthy first-degree relatives of control probands (rMD−). Second, in a double-blinded placebo-controlled randomized trial we investigated whether a 4-week intervention with the selective serotonergic reuptake inhibitor (SSRI) escitalopram had a normalizing effect on behavior and brain responses of the rMD+ individuals.

Results

Negative outcomes increased the probability of risk-averse choices in the subsequent trial in rMD+ but not in rMD− individuals. The orbitofrontal cortex (OFC) displayed a stronger neural response when subjects missed a large reward after a low-risk choice in the rMD+ group compared to the rMD− group. The enhanced orbitofrontal response to negative outcomes was reversed following escitalopram intervention compared to placebo. Conversely, for positive outcomes, the left hippocampus showed attenuated response to high wins in the rMD+ compared to the rMD− group. The SSRI intervention reinforced the hippocampal response to large wins. A subsequent structural analysis revealed that the abnormal neural responses were not accounted for by changes in gray matter density in rMD+ individuals.

Conclusions

Our study in first-degree relatives of depressive patients showed abnormal brain responses to aversive and rewarding outcomes in regions known to be dysfunctional in depression. We further confirmed the reversal of these aberrant activations with SSRI intervention.

Keywords

Decision makingdepressionescitaloprampharmacological MRIrewardSSRI
Type
Original Articles
Information
Psychological Medicine , Volume 44 , Issue 6 , April 2014 , pp. 1183 - 1195
Copyright
Copyright © Cambridge University Press 2013 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Anderson, IM, Juhasz, G, Thomas, E, Downey, D, McKie, S, Deakin, JFW, Elliott, R (2011). The effect of acute citalopram on face emotion processing in remitted depression: a pharmacoMRI study. European Neuropsychopharmacology 21, 140–148.Google Scholar
Baaré, WFC, Vinberg, M, Knudsen, GM, Paulson, OB, Langkilde, AR, Jernigan, TL, Kessing, LV (2010). Hippocampal volume changes in healthy subjects at risk of unipolar depression. Journal of Psychiatric Research 44, 655–662.CrossRefGoogle ScholarPubMed
Boorman, ED, Behrens, TE, Rushworth, MF (2011). Counterfactual choice and learning in a neural network centered on human lateral frontopolar cortex. PLoS Biology 9, e1001093.CrossRefGoogle Scholar
Boorman, ED, Behrens, TEJ, Woolrich, MW, Rushworth, MFS (2009). How green is the grass on the other side? Frontopolar cortex and the evidence in favor of alternative courses of action. Neuron 62, 733–743.Google Scholar
Bylsma, LM, Morris, BH, Rottenberg, J (2008). A meta-analysis of emotional reactivity in major depressive disorder. Clinical Psychology Review 28, 676–691.Google Scholar
Carballedo, A, Lisiecka, D, Fagan, A, Saleh, K, Ferguson, Y, Connolly, G, Meaney, J, Frodl, T (2012). Early life adversity is associated with brain changes in subjects at family risk for depression. World Journal of Biological Psychiatry 13, 569–578.Google Scholar
Coryell, W, Endicott, J, Keller, M (1992). Major depression in a nonclinical sample. Demographic and clinical risk factors for first onset. Archives of General Psychiatry 49, 117–125.CrossRefGoogle Scholar
Deichmann, R, Gottfried, JA, Hutton, C, Turner, R (2003). Optimized EPI for fMRI studies of the orbitofrontal cortex. NeuroImage 19, 430–441.CrossRefGoogle ScholarPubMed
Drevets, WC (2007). Orbitofrontal cortex function and structure in depression. Annals of the New York Academy of Sciences 1121, 499–527.CrossRefGoogle ScholarPubMed
Drevets, WC, Gadde, K, Krishnan, KRR (2004). Neuroimaging studies of depression. In The Neurobiological Foundation of Mental Illness, 2nd edn (ed. Charney, D. S., Nestler, E. and Bunney, B. J.), pp. 461–490. Oxford University Press: New York.Google Scholar
Femenía, T, Gómez-Galán, M, Lindskog, M, Magara, S (2012). Dysfunctional hippocampal activity affects emotion and cognition in mood disorders. Brain Research 1476, 58–70.Google Scholar
Frokjaer, VG, Vinberg, M, Erritzoe, D, Svarer, C, Baaré, W, Budtz-Joergensen, E, Madsen, K, Madsen, J, Kessing, LV, Knudsen, GM (2009). High familial risk for mood disorder is associated with low dorsolateral prefrontal cortex serotonin transporter binding. NeuroImage 46, 360–366.CrossRefGoogle ScholarPubMed
Glover, GH, Li, TQ, Ress, D (2000). Image-based method for retrospective correction of physiological motion effects in fMRI: RETROICOR. Magnetic Resonance in Medicine 44, 162–167.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
Goodnick, PJ, Goldstein, BJ (1998). Selective serotonin reuptake inhibitors in affective disorders: I. Basic pharmacology. Journal of Psychopharmacology 12, S5–S20.Google Scholar
Gotlib, IH, Hamilton, JP, Cooney, RE, Singh, MK, Henry, ML, Joormann, J (2010). Neural processing of reward and loss in girls at risk for major depression. Archives of General Psychiatry 67, 380–387.CrossRefGoogle ScholarPubMed
Haastrup, E, Knorr, U, Erikstrup, C, Kessing, LV, Ullum, H (2012). No evidence for an anti-inflammatory effect of escitalopram intervention in healthy individuals with a family history of depression. Journal of Neuroimmunology 243, 69–72.CrossRefGoogle ScholarPubMed
Hamilton, M (1959). The assessment of anxiety states by rating. British Journal of Medical Psychology 32, 50–55.Google Scholar
Hamilton, M (1980). Rating depressive patients. Journal of Clinical Psychiatry 41, 21–24.Google ScholarPubMed
Henriques, JB, Davidson, RJ (2000). Decreased responsiveness to reward in depression. Cognition and Emotion 14, 711–724.Google Scholar
Kendler, KS, Gardner, CO, Prescott, CA (1999). Clinical characteristics of major depression that predict risk of depression in relatives. Archives of General Psychiatry 56, 322–327.Google Scholar
Knorr, U, Vinberg, M, Gade, A, Winkel, P, Gluud, C, Wetterslev, J, Gether, U, Kessing, L (2011 a). A randomized trial of the effect of escitalopram versus placebo on cognitive function in healthy first-degree relatives of patients with depression. Therapeutic Advances in Psychopharmacology 1, 133–144.Google Scholar
Knorr, U, Vinberg, M, Gether, U, Winkel, P, Gluud, C, Wetterslev, J, Kessing, LV (2012 a). The effect of escitalopram versus placebo on perceived stress and salivary cortisol in healthy first-degree relatives of patients with depression – a randomised trial. Psychiatry Research 200, 354–360.Google Scholar
Knorr, U, Vinberg, M, Hansen, A, Klose, M, Feldt-Rasmussen, U, Hilsted, L, Hasselstrøm, J, Gether, U, Winkel, P, Gluud, C, Wetterslev, J, Kessing, LV (2011 b). Escitalopram and neuroendocrine response in healthy first-degree relatives to depressed patients – a randomized placebo-controlled trial. PloS One 6, e21224.Google Scholar
Knorr, U, Vinberg, M, Klose, M, Feldt-Rasmussen, U, Hilsted, L, Gade, A, Haastrup, E, Paulson, O, Wetterslev, J, Gluud, C, Gether, U, Kessing, L (2009). Rationale and design of the participant, investigator, observer, and data-analyst-blinded randomized AGENDA trial on associations between gene-polymorphisms, endophenotypes for depression and antidepressive intervention: the effect of escitalopram versus placebo on the combined dexamethasone-corticotrophine releasing hormone test and other potential endophenotypes in healthy first-degree relatives of persons with depression. Trials 10, 66.Google Scholar
Knorr, U, Vinberg, M, Mortensen, EL, Winkel, P, Gluud, C, Wetterslev, J, Gether, U, Kessing, LV (2012 b). Effect of chronic escitalopram versus placebo on personality traits in healthy first-degree relatives of patients with depression: a randomized trial. PLoS One 7, e31980.CrossRefGoogle ScholarPubMed
Lisiecka, DM, Carballedo, A, Fagan, AJ, Connolly, G, Meaney, J, Frodl, T (2012). Altered inhibition of negative emotions in subjects at family risk of major depressive disorder. Journal of Psychiatric Research 46, 181–188.Google Scholar
Liu, X, Powell, DK, Wang, H, Gold, BT, Corbly, CR, Joseph, JE (2007). Functional dissociation in frontal and striatal areas for processing of positive and negative reward information. Journal of Neuroscience 27, 4587–4597.Google Scholar
Lund, TE, Madsen, KH, Sidaros, K, Luo, W-L, Nichols, TE (2006). Non-white noise in fMRI: does modelling have an impact? NeuroImage 29, 54–66.Google Scholar
Macoveanu, J, Rowe, JB, Hornboll, B, Elliott, R, Paulson, OB, Knudsen, GM, Siebner, HR (2012). Playing it safe but losing anyway: serotonergic signaling of negative outcomes in dorsomedial prefrontal cortex in the context of risk-aversion. European Neuropsychopharmacology. Published online: 7 10 2012 . doi:10.1016/j.euroneuro.2012.09.006.Google ScholarPubMed
Maldjian, JA, Laurienti, PJ, Kraft, RA, Burdette, JH (2003). An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage 19, 1233–1239.CrossRefGoogle ScholarPubMed
Mannie, ZN, Taylor, MJ, Harmer, CJ, Cowen, PJ, Norbury, R (2011). Frontolimbic responses to emotional faces in young people at familial risk of depression. Journal of Affective Disorders 130, 127–132.Google Scholar
McCabe, C, Mishor, Z, Cowen, PJ, Harmer, CJ (2010). Diminished neural processing of aversive and rewarding stimuli during selective serotonin reuptake inhibitor treatment. Biological Psychiatry 67, 439–445.CrossRefGoogle ScholarPubMed
McNair, PM, Lorr, M DL (1971). Profile of Mood States Manual. Educational and Industrial Testing Service: San Diego, CA.Google Scholar
O'Doherty, JP (2004). Reward representations and reward-related learning in the human brain: insights from neuroimaging. Current Opinion in Neurobiology 14, 769–776.Google Scholar
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 Psychiatric Research 43, 76–87.Google Scholar
Robinson, OJ, Cools, R, Sahakian, BJ (2012). Tryptophan depletion disinhibits punishment but not reward prediction: implications for resilience. Psychopharmacology (Berlin) 219, 599–605.CrossRefGoogle Scholar
Rogers, RD, Tunbridge, EM, Bhagwagar, Z, Drevets, WC, Sahakian, BJ, Carter, CS (2003). Tryptophan depletion alters the decision-making of healthy volunteers through altered processing of reward cues. Neuropsychopharmacology 28, 153–162.Google Scholar
Schultz, W (1998). Predictive reward signal of dopamine neurons. Journal of Neurophysiology 80, 1–27.Google Scholar
Sloan, DM, Strauss, ME, Wisner, KL (2001). Diminished response to pleasant stimuli by depressed women. Journal of Abnormal Psychology 110, 488–493.Google Scholar
Smoski, MJ, Lynch, TR, Rosenthal, MZ, Cheavens, JS, Chapman, AL, Krishnan, RR (2008). Decision-making and risk aversion among depressive adults. Journal of Behavior Therapy and Experimental Psychiatry 39, 567–576.CrossRefGoogle ScholarPubMed
Smoski, MJ, Rittenberg, A, Dichter, GS (2011). Major depressive disorder is characterized by greater reward network activation to monetary than pleasant image rewards. Psychiatry Research 194, 263–270.Google Scholar
Steele, JD, Kumar, P, Ebmeier, KP (2007). Blunted response to feedback information in depressive illness. Brain: A Journal of Neurology 130, 2367–2374.Google Scholar
Sullivan, PF, Neale, MC, Kendler, KS (2000). Genetic epidemiology of major depression: review and meta-analysis. American Journal of Psychiatry 157, 1552–1562.Google Scholar
Tao, R, Calley, CS, Hart, J, Mayes, TL, Nakonezny, PA, Lu, H, Kennard, BD, Tamminga, CA, Emslie, GJ (2012). Brain activity in adolescent major depressive disorder before and after fluoxetine treatment. American Journal of Psychiatry 169, 381–388.Google Scholar
Tzourio-Mazoyer, N, Landeau, B, Papathanassiou, D, Crivello, F, Etard, O, Delcroix, N, Mazoyer, B, Joliot, M (2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. NeuroImage 15, 273–289.Google Scholar
Videbech, P, Ravnkilde, B (2004). Hippocampal volume and depression: a meta-analysis of MRI studies. American Journal of Psychiatry 161, 1957–1966.Google Scholar
Weissman, MM, Wickramaratne, P, Adams, PB, Lish, JD, Horwath, E, Charney, D, Woods, SW, Leeman, E, Frosch, E (1993). The relationship between panic disorder and major depression. A new family study. Archives of General Psychiatry 50, 767–780.Google Scholar
Wing, JK, Babor, T, Brugha, T, Burke, J, Cooper, JE, Giel, R, Jablenski, A, Regier, D, Sartorius, N (1990). SCAN. Schedules for Clinical Assessment in Neuropsychiatry. Archives of General Psychiatry 47, 589–593.Google Scholar