Striatum-related functional activation during reward- versus punishment-based learning in psychosis risk


Psychosis is strongly related to increased striatal dopamine. However, the neural consequences of increased striatal dopamine in psychosis risk are still not fully understood. Consistent with an increase in striatal dopamine, in previous research, psychosis risk has been associated with neural EEG evidence of a greater response to unexpected reward than unexpected punishment feedback on a reversal-learning task. However, previous research has not directly examined whether psychosis risk is associated with altered striatal activation when receiving unexpected feedback on this task. There were two groups of participants: an antipsychotic medication-naive psychosis risk group (n = 21) who had both (a) extreme levels of self-reported psychotic-like beliefs and experiences and (b) interview-rated current-attenuated psychotic symptoms; and a comparison group (n = 20) who had average levels of self-reported psychotic-like beliefs and experiences. Participants completed a reversal-leaning task during fMRI scanning. As expected, in both ROI and whole-brain analyses, the psychosis risk group exhibited greater striatal activation (for whole-brain analyses, the peak was located in the right caudate) to unexpected reward than unexpected punishment feedback relative to the comparison group. These results indicate that psychosis risk is associated with a relatively increased neural sensitivity to unexpected reward than unexpected punishment outcomes and appears consistent with increased striatal dopamine. The results may help us better understand and detect striatal dysfunction in psychosis risk.

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  1. 1.

    Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III-the final common pathway. Schizophr Bull. 2009;35:549–62.

  2. 2.

    Kesby JP, Eyles DW, McGrath JJ, Scott JG. Dopamine, psychosis and schizophrenia: the widening gap between basic and clinical neuroscience. Transl Psychiatry. 2018;8:30.

  3. 3.

    McGlashan TH. Commentary: progress, issues, and implications of prodromal research: an inside view. Schizophr Bull. 2003;29:851–8.

  4. 4.

    Fusar-Poli P, Howes OD, Allen P, Broome M, Valli I, Asselin MC, et al. Abnormal prefrontal activation directly related to pre-synaptic striatal dopamine dysfunction in people at clinical high risk for psychosis. Mol Psychiatry. 2011;16:67–75.

  5. 5.

    Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry. 2009;66:13–20.

  6. 6.

    Frank MJ. Dynamic dopamine modulation in the basal ganglia: a neurocomputational account of cognitive deficits in medicated and nonmedicated Parkinsonism. J Cognit Neurosci. 2005;17:51–72.

  7. 7.

    Klanker M, Sandberg T, Joosten R, Willuhn I, Feenstra M, Denys D. Phasic dopamine release induced by positive feedback predicts individual differences in reversal learning. Neurobiol Learn Mem. 2015;125:135–45.

  8. 8.

    Frank MJ, Seeberger LC, O’Reilly RC. By carrot or by stick: cognitive reinforcement learning in parkinsonism. Science. 2004;306:1940–3.

  9. 9.

    Tai LH, Lee AM, Benavidez N, Bonci A, Wilbrecht L. Transient stimulation of distinct subpopulations of striatal neurons mimics changes in action value. Nat Neurosci. 2012;15:1281–9.

  10. 10.

    Gerfen CR. Basal Ganglia. In: Paxinos G, editor. The Rat Nervous System (Third Edition) Burlington: Academic Press. 2004; 455–508.

  11. 11.

    Nelson AB, Kreitzer AC. Reassessing models of basal ganglia function and dysfunction. Annu Rev Neurosci. 2014;37:117–35.

  12. 12.

    Gerfen CR, Surmeier DJ. Modulation of striatal projection systems by dopamine. Annu Rev Neurosci. 2011;34:441–66.

  13. 13.

    Marcott PF, Gong S, Donthamsetti P, Grinnell SG, Nelson MN, Newman AH, et al. Regional heterogeneity of D2-receptor signaling in the dorsal striatum and nucleus accumbens. Neuron. 2018;98:575–87.e4.

  14. 14.

    Nelson AB, Hammack N, Yang CF, Shah NM, Seal RP, Kreitzer AC. Striatal cholinergic interneurons drive GABA release from dopamine terminals. Neuron. 2014;82:63–70.

  15. 15.

    Maia TV, Frank MJ. An integrative perspective on the role of dopamine in schizophrenia. Biol Psychiatry. 2017;81:52–66.

  16. 16.

    Karcher NR, Bartholow BD, Martin EA, Kerns JG. Associations between electrophysiological evidence of reward and punishment-based learning and psychotic experiences and social anhedonia in at-risk groups. Neuropsychopharmacology. 2017;42:925–32.

  17. 17.

    Cools R, Frank MJ, Gibbs SE, Miyakawa A, Jagust W, D’Esposito M. Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration. J Neurosci. 2009;29:1538–43.

  18. 18.

    San Martin R. Event-related potential studies of outcome processing and feedback-guided learning. Front Hum Neurosci. 2012;6:304.

  19. 19.

    Ermakova AO, Knolle F, Justicia A, Bullmore ET, Jones PB, Robbins TW, et al. Abnormal reward prediction-error signalling in antipsychotic naive individuals with first-episode psychosis or clinical risk for psychosis. Neuropsychopharmacology. 2018;43:1619–99.

  20. 20.

    Schmidt A, Antoniades M, Allen P, Egerton A, Chaddock CA, Borgwardt S, et al. Longitudinal alterations in motivational salience processing in ultra-high-risk subjects for psychosis. Psychol Med. 2017;47:243–54.

  21. 21.

    Radua J, Schmidt A, Borgwardt S, Heinz A, Schlagenhauf F, McGuire P, et al. Ventral striatal activation during reward processing in psychosis: a neurofunctional meta-analysis. JAMA Psychiatry. 2015;72:1243–51.

  22. 22.

    Strauss GP, Cohen AS. A transdiagnostic review of negative symptom phenomenology and etiology. Schizophr Bull. 2017;43:712–9.

  23. 23.

    Ermel JA, Moran EK, Culbreth AJ, Barch DM. Psychotic like experiences as part of a continuum of psychosis: associations with effort-based decision-making and reward responsivity. Schizophr Res. 2018;206:307–12.

  24. 24.

    Karcher NR, Martin EA, Kerns JG. Examining associations between psychosis risk, social anhedonia, and performance of striatum-related behavioral tasks. J Abnorm Psychol. 2015;124:507–18.

  25. 25.

    Karcher NR, Hua JPY, Kerns JG. Probabilistic category learning and striatal functional activation in psychosis risk. Schizophr Bull. 2018;45:396–404.

  26. 26.

    Chapman LJ, Chapman JP, Raulin ML. Body-image aberration in schizophrenia. J Abnorm Psychol. 1978;87:399–407.

  27. 27.

    Eckblad M, Chapman LJ. Magical ideation as an indicator of schizotypy. J Consult Clin Psychol. 1983;51:215–25.

  28. 28.

    Miller TJ, McGlashan TH, Rosen JL, Cadenhead K, Cannon T, Ventura J, et al. Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability. Schizophr Bull. 2003;29:703–15.

  29. 29.

    Chapman LJ, Chapman JP, Kwapil TR, Eckblad M, Zinser MC. Putatively psychosis-prone subjects 10 years later. J Abnorm Psychol. 1994;103:171–83.

  30. 30.

    Pedersen CB, Mors O, Bertelsen A, Waltoft BL, Agerbo E, McGrath JJ, et al. A comprehensive nationwide study of the incidence rate and lifetime risk for treated mental disorders. JAMA Psychiatry. 2014;71:573–81.

  31. 31.

    Faridi K, Pawliuk N, King S, Joober R, Malla AK. Prevalence of psychotic and non-psychotic disorders in relatives of patients with a first episode psychosis. Schizophr Res. 2009;114:57–63.

  32. 32.

    Karcher NR, Cicero DC, Kerns JG. An experimental examination of the aberrant salience hypothesis using a salience manipulation and a behavioral magical thinking task. J Exp Psychopathol. 2015;6.jep.041814.

  33. 33.

    Smith SM, Jenkinson M, Woolrich MW, Beckmann CF, Behrens TE, Johansen-Berg H, et al. Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage. 2004;23(Suppl 1):S208–19.

  34. 34.

    Jenkinson M, Bannister P, Brady M, Smith S. Improved optimization for the robust and accurate linear registration and motion correction of brain images. Neuroimage. 2002;17:825–41.

  35. 35.

    Woo C-W, Krishnan A, Wager TD. Cluster-extent based thresholding in fMRI analyses: pitfalls and recommendations. Neuroimage. 2014;91:412–9.

  36. 36.

    Yeo BT, Krienen FM, Sepulcre J, Sabuncu MR, Lashkari D, Hollinshead M, et al. The organization of the human cerebral cortex estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106:1125–65.

  37. 37.

    Choi EY, Yeo BT, Buckner RL. The organization of the human striatum estimated by intrinsic functional connectivity. J Neurophysiol. 2012;108:2242–63.

  38. 38.

    Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36:1–48.

  39. 39.

    Cox SM, Frank MJ, Larcher K, Fellows LK, Clark CA, Leyton M, et al. Striatal D1 and D2 signaling differentially predict learning from positive and negative outcomes. Neuroimage. 2015;109:95–101.

  40. 40.

    Lancaster TM, Linden DE, Tansey KE, Banaschewski T, Bokde AL, Bromberg U, et al. Polygenic risk of psychosis and ventral striatal activation during reward processing in healthy adolescents. JAMA Psychiatry. 2016;73:852–61.

  41. 41.

    Wotruba D, Heekeren K, Michels L, Buechler R, Simon JJ, Theodoridou A, et al. Symptom dimensions are associated with reward processing in unmedicated persons at risk for psychosis. Front Behav Neurosci. 2014;8:382.

  42. 42.

    Winton-Brown T, Schmidt A, Roiser JP, Howes OD, Egerton A, Fusar-Poli P, et al. Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis. Transl Psychiatry. 2017;7:e1245.

  43. 43.

    Taylor N, Hollis JP, Corcoran S, Gross R, Cuthbert B, Swails LW, et al. Impaired reward responsiveness in schizophrenia. Schizophr Res. 2018;199:46–52.

  44. 44.

    Morris RW, Vercammen A, Lenroot R, Moore L, Langton JM, Short B, et al. Disambiguating ventral striatum fMRI-related BOLD signal during reward prediction in schizophrenia. Mol Psychiatry. 2012;17:235. 80–9.

  45. 45.

    Murray GK, Corlett PR, Clark L, Pessiglione M, Blackwell AD, Honey G, et al. Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. Mol Psychiatry. 2008;13:239. 67–76.

  46. 46.

    Schlagenhauf F, Huys QJ, Deserno L, Rapp MA, Beck A, Heinze HJ, et al. Striatal dysfunction during reversal learning in unmedicated schizophrenia patients. Neuroimage. 2014;89:171–80.

  47. 47.

    Reinen JM, Van Snellenberg JX, Horga G, Abi-Dargham A, Daw ND, Shohamy D. Motivational context modulates prediction error response in schizophrenia. Schizophr Bull. 2016;42:1467–75.

  48. 48.

    Millman ZB, Gallagher K, Demro C, Schiffman J, Reeves GM, Gold JM, et al. Evidence of reward system dysfunction in youth at clinical high-risk for psychosis from two event-related fMRI paradigms. Schizophr Res. (pii: S0920-9964(19)30111-2 2019. [E-pub ahead of print].

  49. 49.

    Vo A, Seergobin KN, Morrow SA, MacDonald PA. Levodopa impairs probabilistic reversal learning in healthy young adults. Psychopharmacology. 2016;233:2753–63.

  50. 50.

    Robbins TW, Cools R. Cognitive deficits in Parkinson’s disease: a cognitive neuroscience perspective. Mov Disord. 2014;29:597–607.

  51. 51.

    Moody TD, Bookheimer SY, Vanek Z, Knowlton BJ. An implicit learning task activates medial temporal lobe in patients with Parkinson’s disease. Behav Neurosci. 2004;118:438–42.

  52. 52.

    Samaha AN, Seeman P, Stewart J, Rajabi H, Kapur S. “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci. 2007;27:2979–86.

  53. 53.

    Goldman AL, Pezawas L, Mattay VS, Fischl B, Verchinski BA, Zoltick B, et al. Heritability of brain morphology related to schizophrenia: a large-scale automated magnetic resonance imaging segmentation study. Biol Psychiatry. 2008;63:475–83.

  54. 54.

    van Haren NE, Hulshoff Pol HE, Schnack HG, Cahn W, Mandl RC, Collins DL, et al. Focal gray matter changes in schizophrenia across the course of the illness: a 5-year follow-up study. Neuropsychopharmacology. 2007;32:2057–66.

  55. 55.

    Demjaha A, Murray RM, McGuire PK, Kapur S, Howes OD. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. Am J Psychiatry. 2012;169:1203–10.

  56. 56.

    Button KS, Ioannidis JP, Mokrysz C, Nosek BA, Flint J, Robinson ES, et al. Power failure: why small sample size undermines the reliability of neuroscience. Nat Rev Neurosci. 2013;14:365–76.

  57. 57.

    Martz ME, Trucco EM, Cope LM, Hardee JE, Jester JM, Zucker RA, et al. Association of marijuana use with blunted nucleus accumbens response to reward anticipation. JAMA Psychiatry. 2016;73:838–44.

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Funding and Disclosure

The authors declare that there are no conflicts of interest in relation to the subject of this study. This research was supported by the National Institute of Mental Health (T32 MH014677 to NRK and MH100359 to JGK) and by the University of Missouri research funds (to JGK).

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Correspondence to Nicole R. Karcher.

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Karcher, N.R., Hua, J.P.Y. & Kerns, J.G. Striatum-related functional activation during reward- versus punishment-based learning in psychosis risk. Neuropsychopharmacol. 44, 1967–1974 (2019).

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