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Neuroscience of apathy and anhedonia: a transdiagnostic approach

Nature Reviews Neurosciencevolume 19pages470484 (2018) | Download Citation


Apathy and anhedonia are common syndromes of motivation that are associated with a wide range of brain disorders and have no established therapies. Research using animal models suggests that a useful framework for understanding motivated behaviour lies in effort-based decision making for reward. The neurobiological mechanisms underpinning such decisions have now begun to be determined in individuals with apathy or anhedonia, providing an important foundation for developing new treatments. The findings suggest that there might be some shared mechanisms between both syndromes. A transdiagnostic approach that cuts across traditional disease boundaries provides a potentially useful means for understanding these conditions.

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  1. 1.

    Caeiro, L., Ferro, J. M. & Costa, J. Apathy secondary to stroke: a systematic review and meta-analysis. Cerebrovasc. Dis. 35, 23–39 (2013).

  2. 2.

    Starkstein, S. E. & Pahissa, J. Apathy following traumatic brain injury. Psychiatr. Clin. North Am. 37, 103–112 (2014).

  3. 3.

    Seel, R. T. et al. Depression after traumatic brain injury: a National Institute on Disability and Rehabilitation Research Model Systems multicenter investigation. Arch. Phys. Med. Rehabil. 84, 177–184 (2003).

  4. 4.

    Zhao, Q.-F. et al. The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. J. Affect. Disord. 190, 264–271 (2016).

  5. 5.

    Lopez, O. L. et al. Psychiatric symptoms vary with the severity of dementia in probable Alzheimer’s disease. J. Neuropsychiatry Clin. Neurosci. 15, 346–353 (2003).

  6. 6.

    den Brok, M. G. H. E. et al. Apathy in Parkinson’s disease: a systematic review and meta-analysis. Mov. Disord. 30, 759–769 (2015).

  7. 7.

    Lemke, M. R., Brecht, H. M., Koester, J., Kraus, P. H. & Reichmann, H. Anhedonia, depression, and motor functioning in Parkinson’s disease during treatment with pramipexole. J. Neuropsychiatry Clin. Neurosci. 17, 214–220 (2005).

  8. 8.

    Staekenborg, S. S. et al. Behavioural and psychological symptoms in vascular dementia; differences between small- and large-vessel disease. J. Neurol. Neurosurg. Psychiatry 81, 547–551 (2010).

  9. 9.

    Chow, T. W. et al. Apathy symptom profile and behavioral associations in frontotemporal dementia versus dementia of Alzheimer type. Arch. Neurol. 66, 888–893 (2009).

  10. 10.

    van Duijn, E. et al. Neuropsychiatric symptoms in a European Huntington’s disease cohort (REGISTRY). J. Neurol. Neurosurg. Psychiatry 85, 1411–1418 (2014).

  11. 11.

    Pelizza, L. & Ferrari, A. Anhedonia in schizophrenia and major depression: state or trait? Ann. Gen. Psychiatry 8, 22 (2009).

  12. 12.

    Yuen, G. S. et al. Apathy in late-life depression: common, persistent, and disabling. Am. J. Geriatr. Psychiatry 23, 488–494 (2015).

  13. 13.

    Horan, W. P., Kring, A. M. & Blanchard, J. J. Anhedonia in schizophrenia: a review of assessment strategies. Schizophr. Bull. 32, 259–273 (2006).

  14. 14.

    Yazbek, H. et al. The Lille Apathy Rating Scale (LARS): exploring its psychometric properties in schizophrenia. Schizophr. Res. 157, 278–284 (2014).

  15. 15.

    Brown, R. G. & Pluck, G. Negative symptoms: the ‘pathology’ of motivation and goal-directed behaviour. Trends Neurosci. 23, 412–417 (2000).

  16. 16.

    Prange, S. et al. Historical crossroads in the conceptual delineation of apathy in Parkinson’s disease. Brain 141, 613–619 (2018).

  17. 17.

    Starkstein, S. E. & Leentjens, A. F. G. The nosological position of apathy in clinical practice. J. Neurol. Neurosurg. Psychiatry 79, 1088–1092 (2008).

  18. 18.

    Lanctôt, K. L. et al. Apathy associated with neurocognitive disorders: recent progress and future directions. Alzheimers Dement. 13, 84–100 (2017).

  19. 19.

    Robert, P. et al. Proposed diagnostic criteria for apathy in Alzheimer’s disease and other neuropsychiatric disorders. Eur. Psychiatry 24, 98–104 (2009).

  20. 20.

    Thomsen, K. R., Whybrow, P. C. & Kringelbach, M. L. Reconceptualizing anhedonia: novel perspectives on balancing the pleasure networks in the human brain. Front. Behav. Neurosci. 9, 49 (2015).

  21. 21.

    Foussias, G. & Remington, G. Negative symptoms in schizophrenia: avolition and Occam’s razor. Schizophr. Bull. 36, 359–369 (2010).

  22. 22.

    Treadway, M. T. & Zald, D. H. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci. Biobehav. Rev. 35, 537–555 (2011). This helpful overview provides mechanistic insights on anhedonia in human depression.

  23. 23.

    Berridge, K. C. & Robinson, T. E. Parsing reward. Trends Neurosci. 26, 507–513 (2003).

  24. 24.

    Barch, D. M., Pagliaccio, D. & Luking, K. Mechanisms underlying motivational deficits in psychopathology: similarities and differences in depression and schizophrenia. Curr. Top. Behav. Neurosci. 27, 411–449 (2016). This is a comprehensive current review of evidence for possible underlying behavioural components of amotivation across depression and schizophrenia.

  25. 25.

    Der-Avakian, A., Barnes, S. A., Markou, A. & Pizzagalli, D. A. Translational assessment of reward and motivational deficits in psychiatric disorders. Curr. Top. Behav. Neurosci. 28, 231–262 (2015). This overview relates animal models to human disorders of motivation in psychiatric diagnoses.

  26. 26.

    Salamone, J. D., Yohn, S. E., López-Cruz, L., San Miguel, N. & Correa, M. Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology. Brain 139, 1325–1347 (2016). This is a comprehensive review of animal and human experiments investigating the brain mechanisms of effort-related decision making for reward, and how these relate to anhedonia and apathy.

  27. 27.

    Le Heron, C., Apps, M. A. J. & Husain, M. The anatomy of apathy: a neurocognitive framework for amotivated behaviour. Neuropsychologia (2017). This is a review of neuroimaging studies of apathy across neurological diseases demonstrating many common patterns of regional brain changes.

  28. 28.

    Marin, R. S. Apathy: a neuropsychiatric syndrome. J. Neuropsychiatry Clin. Neurosci. 3, 243–254 (1991).

  29. 29.

    Starkstein, S. E., Petracca, G., Chemerinski, E. & Kremer, J. Syndromic validity of apathy in Alzheimer’s disease. Am. J. Psychiatry 158, 872–877 (2001).

  30. 30.

    Sockeel, P. et al. The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 77, 579–584 (2006).

  31. 31.

    Ang, Y.-S., Lockwood, P., Apps, M. A. J., Muhammed, K. & Husain, M. Distinct subtypes of apathy revealed by the apathy motivation index. PLoS ONE 12, e0169938 (2017).

  32. 32.

    Németh, G., Hegedüs, K. & Molnár, L. Akinetic mutism associated with bicingular lesions: clinicopathological and functional anatomical correlates. Eur. Arch. Psychiatry Neurol. Sci. 237, 218–222 (1988).

  33. 33.

    Rizvi, S. J. et al. Development and validation of the Dimensional Anhedonia Rating Scale (DARS) in a community sample and individuals with major depression. Psychiatry Res. 229, 109–119 (2015).

  34. 34.

    American Psychiatric Association & American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-5 (American Psychiatric Association, WA, 2013).

  35. 35.

    Shankman, S. A. et al. in Anhedonia: A Comprehensive Handbook Volume 1 (ed. Ritsner, M.) 3–22 (Springer, Netherlands, 2014).

  36. 36.

    Assogna, F., Cravello, L., Caltagirone, C. & Spalletta, G. Anhedonia in Parkinson’s disease: a systematic review of the literature. Mov. Disord. 26, 1825–1834 (2011).

  37. 37.

    Blanchard, J. J. & Cohen, A. S. The structure of negative symptoms within schizophrenia: implications for assessment. Schizophr. Bull. 32, 238–245 (2006).

  38. 38.

    Foussias, G., Agid, O., Fervaha, G. & Remington, G. Negative symptoms of schizophrenia: clinical features, relevance to real world functioning and specificity versus other CNS disorders. Eur. Neuropsychopharmacol. 24, 693–709 (2014).

  39. 39.

    Kaiser, S. et al. Individual negative symptoms and domains — relevance for assessment, pathomechanisms and treatment. Schizophr. Res. 186, 39–45 (2017).

  40. 40.

    Bischof, M. et al. The brief negative symptom scale: validation of the German translation and convergent validity with self-rated anhedonia and observer-rated apathy. BMC Psychiatry 16, 415 (2016).

  41. 41.

    Hartmann, M. N. et al. Apathy in schizophrenia as a deficit in the generation of options for action. J. Abnorm. Psychol. 124, 309–318 (2015). This is one of the few studies that have examined the possibility that a deficit in generating options for behaviour might be associated with apathy in humans.

  42. 42.

    Isella, V. et al. Physical anhedonia in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 74, 1308–1311 (2003).

  43. 43.

    Skorvanek, M. et al. The associations between fatigue, apathy, and depression in Parkinson’s disease. Acta Neurol. Scand. 131, 80–87 (2015).

  44. 44.

    Lampe, I. K., Kahn, R. S. & Heeren, T. J. Apathy, anhedonia, and psychomotor retardation in elderly psychiatric patients and healthy elderly individuals. J. Geriatr. Psychiatry Neurol. 14, 11–16 (2001).

  45. 45.

    Brodaty, H., Altendorf, A., Withall, A. & Sachdev, P. Do people become more apathetic as they grow older? A longitudinal study in healthy individuals. Int. Psychogeriatr. 22, 426–436 (2010).

  46. 46.

    Bonnelle, V., Manohar, S., Behrens, T. & Husain, M. Individual differences in premotor brain systems underlie behavioral apathy. Cereb. Cortex 26, bhv247 (2016).

  47. 47.

    Lavretsky, H. et al. The MRI brain correlates of depressed mood, anhedonia, apathy, and anergia in older adults with and without cognitive impairment or dementia. Int. J. Geriatr. Psychiatry 23, 1040–1050 (2008).

  48. 48.

    Grool, A. M. et al. Structural MRI correlates of apathy symptoms in older persons without dementia: AGES-Reykjavik Study. Neurology 82, 1628–1635 (2014).

  49. 49.

    Kawagoe, T., Onoda, K. & Yamaguchi, S. Apathy and executive function in healthy elderly — resting state fMRI study. Front. Aging Neurosci. 9, 124 (2017).

  50. 50.

    Rzepa, E., Fisk, J. & McCabe, C. Blunted neural response to anticipation, effort and consummation of reward and aversion in adolescents with depression symptomatology. J. Psychopharmacol. 31, 303–311 (2017).

  51. 51.

    Pessiglione, M., Vinckier, F., Bouret, S., Daunizeau, J. & Le Bouc, R. Why not try harder? Computational approach to motivation deficits in neuro-psychiatric diseases. Brain (2017).

  52. 52.

    Sinha, N., Manohar, S. & Husain, M. Impulsivity and apathy in Parkinson’s disease. J. Neuropsychol. 7, 255–283 (2013).

  53. 53.

    Ang, Y.-S. et al. Dopamine modulates option generation for behaviour. Curr. Biol. 28, 1561–1569 (2018).

  54. 54.

    Robinson, G., Shallice, T., Bozzali, M. & Cipolotti, L. The differing roles of the frontal cortex in fluency tests. Brain 135, 2202–2214 (2012).

  55. 55.

    Glimcher, P. W., Fehr, E. & Camerer, C. (eds). Neuroeconomics: Decision Making and The Brain. (Elsevier Academic Press, London, 2014).

  56. 56.

    Le Bouc, R. et al. Computational dissection of dopamine motor and motivational functions in humans. J. Neurosci. 36, 6623–6633 (2016). This study combines empirical findings with computational modelling to pinpoint impaired reward processing in Parkinson's disease.

  57. 57.

    Le Heron, C. et al. Distinct effects of apathy and dopamine on effort-based decision-making in Parkinson’s disease. Brain 141, 1455–1469 (2018).

  58. 58.

    Brehm, J. W. & Self, E. A. The intensity of motivation. Annu. Rev. Psychol. 40, 109–131 (1989).

  59. 59.

    Muhammed, K. et al. Reward sensitivity deficits modulated by dopamine are associated with apathy in Parkinson’s disease. Brain 139, 2706–2721 (2016).

  60. 60.

    Salamone, J. D., Cousins, M. S. & Bucher, S. Anhedonia or anergia? Effects of haloperidol and nucleus accumbens dopamine depletion on instrumental response selection in a T-maze cost/benefit procedure. Behav. Brain Res. 65, 221–229 (1994).

  61. 61.

    Treadway, M. T., Bossaller, N. A., Shelton, R. C. & Zald, D. H. Effort-based decision-making in major depressive disorder: a translational model of motivational anhedonia. J. Abnorm. Psychol. 121, 553–558 (2012).

  62. 62.

    Chong, T. T.-J. et al. Dopamine enhances willingness to exert effort for reward in Parkinson’s disease. Cortex 69, 40–46 (2015).

  63. 63.

    Murray, G. K. et al. Incentive motivation in first-episode psychosis: a behavioural study. BMC Psychiatry 8, 34 (2008).

  64. 64.

    Hosking, J. G., Cocker, P. J. & Winstanley, C. A. Dissociable contributions of anterior cingulate cortex and basolateral amygdala on a rodent cost/benefit decision-making task of cognitive effort. Neuropsychopharmacology 39, 1558–1567 (2014).

  65. 65.

    Schmidt, L., Lebreton, M., Cléry-Melin, M.-L., Daunizeau, J. & Pessiglione, M. Neural mechanisms underlying motivation of mental versus physical effort. PLoS Biol. 10, e1001266 (2012).

  66. 66.

    Chong, T. T.-J. et al. Neurocomputational mechanisms underlying subjective valuation of effort costs. PLoS Biol. 15, e1002598 (2017).

  67. 67.

    Berridge, K. C. & Robinson, T. E. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res. Rev. 28, 309–369 (1998). This landmark experimental paper examines the role of DA in appetitive and consummatory reward processing, providing clear evidence that the former, but not the latter, is disrupted by profound DA depletion.

  68. 68.

    Huys, Q. J. M. et al. The specificity of Pavlovian regulation is associated with recovery from depression. Psychol. Med. 46, 1027–1035 (2016).

  69. 69.

    Willner, P. The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiol. Stress 6, 78–93 (2017).

  70. 70.

    Huys, Q. J. M., Daw, N. D. & Dayan, P. Depression: a decision-theoretic analysis. Annu. Rev. Neurosci. 38, 1–23 (2015). This article provides a clear explanation from a computational neuroscience perspective of the different aspects of motivational processing that may underlie depressive symptoms.

  71. 71.

    Bechara, A., Damasio, H., Tranel, D. & Damasio, A. R. Deciding advantageously before knowing the advantageous strategy. Science 275, 1293–1295 (1997).

  72. 72.

    Evens, R., Hoefler, M., Biber, K. & Lueken, U. The Iowa Gambling Task in Parkinson’s disease: a meta-analysis on effects of disease and medication. Neuropsychologia 91, 163–172 (2016).

  73. 73.

    Adams, R. A., Huys, Q. J. M. & Roiser, J. P. Computational psychiatry: towards a mathematically informed understanding of mental illness. J. Neurol. Neurosurg. Psychiatry 87, 53–63 (2016).

  74. 74.

    Henriques, J. B., Glowacki, J. M. & Davidson, R. J. Reward fails to alter response bias in depression. J. Abnorm. Psychol. 103, 460–466 (1994).

  75. 75.

    Huys, Q. J., Pizzagalli, D. A., Bogdan, R. & Dayan, P. Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis. Biol. Mood Anxiety Disord. 3, 12 (2013).

  76. 76.

    Collins, A. G. E., Brown, J. K., Gold, J. M., Waltz, J. A. & Frank, M. J. Working memory contributions to reinforcement learning impairments in Schizophrenia. J. Neurosci. 34, 13747–13756 (2014).

  77. 77.

    Meyniel, F. et al. A specific role for serotonin in overcoming effort cost. eLife 5, e17282 (2016).

  78. 78.

    Levy, R. & Dubois, B. Apathy and the functional anatomy of the prefrontal cortex-basal ganglia circuits. Cereb. Cortex 16, 916–928 (2005).

  79. 79.

    Barris, R. W. & Schuman, H. R. Bilateral anterior cingulate gyrus lesions; syndrome of the anterior cingulate gyri. Neurology 3, 44–52 (1953).

  80. 80.

    Laplane, D. et al. Obsessive-compulsive and other behavioural changes with bilateral basal ganglia lesions. A neuropsychological, magnetic resonance imaging and positron tomography study. Brain 112, 699–725 (1989).

  81. 81.

    Adam, R. et al. Dopamine reverses reward insensitivity in apathy following globus pallidus lesions. Cortex 49, 1292–1303 (2013).

  82. 82.

    Kang, S. Y. & Kim, J. S. Anterior cerebral artery infarction: stroke mechanism and clinical-imaging study in 100 patients. Neurology 70, 2386–2393 (2008).

  83. 83.

    Manohar, S. G. & Husain, M. Human ventromedial prefrontal lesions alter incentivisation by reward. Cortex 76, 104–120 (2016).

  84. 84.

    Heath, R. G. Pleasure and brain activity in man. Deep and surface electroencephalograms during orgasm. J. Nerv. Ment. Dis. 154, 3–18 (1972).

  85. 85.

    Berridge, K. C. & Kringelbach, M. L. Pleasure systems in the brain. Neuron 86, 646–664 (2015).

  86. 86.

    Parvizi, J., Rangarajan, V., Shirer, W. R., Desai, N. & Greicius, M. D. The will to persevere induced by electrical stimulation of the human cingulate gyrus. Neuron 80, 1359–1367 (2013).

  87. 87.

    Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).

  88. 88.

    Holtzheimer, P. E. et al. Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial. Lancet Psychiatry 4, 839–849 (2017).

  89. 89.

    Rudebeck, P. H., Walton, M. E., Smyth, A. N., Bannerman, D. M. & Rushworth, M. F. S. Separate neural pathways process different decision costs. Nat. Neurosci. 9, 1161–1168 (2006).

  90. 90.

    Walton, M. E., Kennerley, S. W., Bannerman, D. M., Phillips, P. E. M. & Rushworth, M. F. S. Weighing up the benefits of work: behavioral and neural analyses of effort-related decision making. Neural Netw. 19, 1302–1314 (2006).

  91. 91.

    Floresco, S. B. & Ghods-Sharifi, S. Amygdala-prefrontal cortical circuitry regulates effort-based decision making. Cereb. Cortex 17, 251–260 (2007).

  92. 92.

    Hauber, W. & Sommer, S. Prefrontostriatal circuitry regulates effort-related decision making. Cereb. Cortex 19, 2240–2247 (2009).

  93. 93.

    Worbe, Y. et al. Behavioral and movement disorders induced by local inhibitory dysfunction in primate striatum. Cereb. Cortex 19, 1844–1856 (2009).

  94. 94.

    Wise, R. A. Addictive drugs and brain stimulation reward. Annu. Rev. Neurosci. 19, 319–340 (1996).

  95. 95.

    Ferenczi, E. A. et al. Prefrontal cortical regulation of brainwide circuit dynamics and reward-related behavior. Science 351, aac9698 (2016). This pioneering experimental study combines fMRI with simultaneous optogenetic stimulation of both DA and mPFC neurons. Stimulating DA neurons increased (and silencing reduced) vStr responses and reward-seeking behaviour, which was blunted by mPFC stimulation.

  96. 96.

    Croxson, P. L., Walton, M. E., O’Reilly, J. X., Behrens, T. E. J. & Rushworth, M. F. S. Effort-based cost-benefit valuation and the human brain. J. Neurosci. 29, 4531–4541 (2009).

  97. 97.

    Skvortsova, V., Palminteri, S. & Pessiglione, M. Learning to minimize efforts versus maximizing rewards: computational principles and neural correlates. J. Neurosci. 34, 15621–15630 (2014).

  98. 98.

    Klein-Flugge, M. C., Kennerley, S. W., Friston, K. & Bestmann, S. Neural signatures of value comparison in human cingulate cortex during decisions requiring an effort-reward trade-off. J. Neurosci. 36, 10002–10015 (2016).

  99. 99.

    Zenon, A., Sidibe, M. & Olivier, E. Disrupting the supplementary motor area makes physical effort appear less effortful. J. Neurosci. 35, 8737–8744 (2015).

  100. 100.

    Kroemer, N. B. et al. Balancing reward and work: anticipatory brain activation in NAcc and VTA predict effort differentially. Neuroimage 102, 510–519 (2014).

  101. 101.

    Kurniawan, I. T., Guitart-Masip, M., Dayan, P. & Dolan, R. J. Effort and valuation in the brain: the effects of anticipation and execution. J. Neurosci. 33, 6160–6169 (2013).

  102. 102.

    Lau, H. C., Rogers, R. D., Haggard, P. & Passingham, R. E. Attention to intention. Science 303, 1208–1210 (2004).

  103. 103.

    Nachev, P., Kennard, C. & Husain, M. Functional role of the supplementary and pre-supplementary motor areas. Nat. Rev. Neurosci. 9, 856–869 (2008).

  104. 104.

    Pizzagalli, D. A. et al. Reduced caudate and nucleus accumbens response to rewards in unmedicated individuals with major depressive disorder. Am. J. Psychiatry 166, 702–710 (2009).

  105. 105.

    Knutson, B., Bhanji, J. P., Cooney, R. E., Atlas, L. Y. & Gotlib, I. H. Neural responses to monetary incentives in major depression. Biol. Psychiatry 63, 686–692 (2008).

  106. 106.

    Gorka, S. M. et al. Neural response to reward anticipation in those with depression with and without panic disorder. J. Affect. Disord. 164, 50–56 (2014).

  107. 107.

    Rutledge, R. B. et al. Association of neural and emotional impacts of reward prediction errors with major depression. JAMA Psychiatry 74, 790 (2017).

  108. 108.

    Stringaris, A. et al. The brain’s response to reward anticipation and depression in adolescence: dimensionality, specificity, and longitudinal predictions in a community-based sample. Am. J. Psychiatry 172, 1215–1223 (2015).

  109. 109.

    Ziauddeen, H. & Murray, G. K. The relevance of reward pathways for schizophrenia. Curr. Opin. Psychiatry 23, 91–96 (2010).

  110. 110.

    Zhang, B. et al. Mapping anhedonia-specific dysfunction in a transdiagnostic approach: an ALE meta-analysis. Brain Imaging Behav. 10, 920–939 (2016).

  111. 111.

    Howe, M. W., Tierney, P. L., Sandberg, S. G., Phillips, P. E. M. & Graybiel, A. M. Prolonged dopamine signalling in striatum signals proximity and value of distant rewards. Nature 500, 575–579 (2013).

  112. 112.

    Robbins, T. W., Roberts, D. C. & Koob, G. F. Effects of D-amphetamine and apomorphine upon operant behavior and schedule-induced licking in rats with 6-hydroxydopamine-induced lesions of the nucleus accumbens. J. Pharmacol. Exp. Ther. 224, 662–673 (1983).

  113. 113.

    Taylor, J. R. & Robbins, T. W. Enhanced behavioural control by conditioned reinforcers following microinjections of d-amphetamine into the nucleus accumbens. Psychopharmacology. 84, 405–412 (1984).

  114. 114.

    Cador, M., Taylor, J. R. & Robbins, T. W. Potentiation of the effects of reward-related stimuli by dopaminergic-dependent mechanisms in the nucleus accumbens. Psychopharmacoloy 104, 377–385 (1991).

  115. 115.

    Salamone, J. D. & Correa, M. The mysterious motivational functions of mesolimbic dopamine. Neuron 76, 470–485 (2012).

  116. 116.

    Schultz, W., Dayan, P. & Montague, P. R. A neural substrate of prediction and reward. Science 275, 1593–1599 (1997).

  117. 117.

    Chang, C. Y. et al. Brief optogenetic inhibition of dopamine neurons mimics endogenous negative reward prediction errors. Nat. Neurosci. 19, 111–116 (2016).

  118. 118.

    Steinberg, E. E. et al. A causal link between prediction errors, dopamine neurons and learning. Nat. Neurosci. 16, 966–973 (2013).

  119. 119.

    Niv, Y., Daw, N. D., Joel, D. & Dayan, P. Tonic dopamine: opportunity costs and the control of response vigor. Psychopharmacology 191, 507–520 (2007).

  120. 120.

    Hamid, A. A. et al. Mesolimbic dopamine signals the value of work. Nat. Neurosci. 19, 117–126 (2015). In this investigation, microdialysis and voltammetry were used to measure DA release in the NAc. DA levels co-varied with reward rate and motivational vigour, and also encoded value. The authors conclude that DA conveys a signal regarding the available reward for investment of effort.

  121. 121.

    Syed, E. C. J. et al. Action initiation shapes mesolimbic dopamine encoding of future rewards. Nat. Neurosci. 19, 34–36 (2015). This study used FSCV to demonstrate that DA is released in the vStr when animals are required to make an action to obtain a reward, and that DA release is attenuated when inhibition of movement is required.

  122. 122.

    Collins, A. G. E. & Frank, M. J. Surprise! Dopamine signals mix action, value and error. Nat. Neurosci. 19, 3–5 (2016).

  123. 123.

    Martins, D., Mehta, M. A. & Prata, D. The “highs and lows” of the human brain on dopaminergics: evidence from neuropharmacology. Neurosci. Biobehav. Rev. 80, 351–371 (2017). This article presents a systematic review of behavioural and neural effects of DA manipulations in humans.

  124. 124.

    Leyton, M. et al. Decreasing amphetamine-induced dopamine release by acute phenylalanine/tyrosine depletion: a PET/[11C]raclopride study in healthy men. Neuropsychopharmacology 29, 427–432 (2003).

  125. 125.

    Roiser, J. P. et al. The subjective and cognitive effects of acute phenylalanine and tyrosine depletion in patients recovered from depression. Neuropsychopharmacology 30, 775–785 (2005).

  126. 126.

    Robinson, O. J., Standing, H. R., DeVito, E. E., Cools, R. & Sahakian, B. J. Dopamine precursor depletion improves punishment prediction during reversal learning in healthy females but not males. Psychopharmacology 211, 187–195 (2010).

  127. 127.

    Bjork, J. M., Grant, S. J., Chen, G. & Hommer, D. W. Dietary tyrosine/phenylalanine depletion effects on behavioral and brain signatures of human motivational processing. Neuropsychopharmacology 39, 595–604 (2014).

  128. 128.

    Guitart-Masip, M. et al. Action controls dopaminergic enhancement of reward representations. Proc. Natl Acad. Sci. USA 109, 7511–7516 (2012).

  129. 129.

    Zenon, A., Devesse, S. & Olivier, E. Dopamine manipulation affects response vigor independently of opportunity cost. J. Neurosci. 36, 9516–9525 (2016).

  130. 130.

    Rutledge, R. B., Skandali, N., Dayan, P. & Dolan, R. J. Dopaminergic modulation of decision making and subjective well-being. J. Neurosci. 35, 9811–9822 (2015).

  131. 131.

    Chowdhury, R. et al. Dopamine restores reward prediction errors in old age. Nat. Neurosci. 16, 648–653 (2013).

  132. 132.

    Argyropoulos, S. V. & Nutt, D. J. Anhedonia revisited: is there a role for dopamine-targeting drugs for depression? J. Psychopharmacol. 27, 869–877 (2013).

  133. 133.

    Di Giannantonio, M. & Martinotti, G. Anhedonia and major depression: the role of agomelatine. Eur. Neuropsychopharmacol. 22, S505–S510 (2012).

  134. 134.

    Thobois, S. et al. Parkinsonian apathy responds to dopaminergic stimulation of D2/D3 receptors with piribedil. Brain 136, 1568–1577 (2013).

  135. 135.

    Devos, D. et al. Rivastigmine in apathetic but dementia and depression-free patients with Parkinson’s disease: a double-blind, placebo-controlled, randomised clinical trial. J. Neurol. Neurosurg. Psychiatry 85, 668–674 (2014).

  136. 136.

    McGirr, A. et al. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol. Med. 45, 693–704 (2015).

  137. 137.

    Kokkinou, M., Ashok, A. H. & Howes, O. D. The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol. Psychiatry 23, 59–69 (2017).

  138. 138.

    Lally, N. et al. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry 4, e469 (2014).

  139. 139.

    Peciña, M. et al. Striatal dopamine D2/3 receptor-mediated neurotransmission in major depression: implications for anhedonia, anxiety and treatment response. Eur. Neuropsychopharmacol. 27, 977–986 (2017).

  140. 140.

    Remy, P., Doder, M., Lees, A., Turjanski, N. & Brooks, D. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain 128, 1314–1322 (2005).

  141. 141.

    Sarchiapone, M. et al. Dopamine transporter binding in depressed patients with anhedonia. Psychiatry Res. 147, 243–248 (2006).

  142. 142.

    Bloomfield, M. A. P., Morgan, C. J. A., Kapur, S., Curran, H. V. & Howes, O. D. The link between dopamine function and apathy in cannabis users: an [18F]-DOPA PET imaging study. Psychopharmacology 231, 2251–2259 (2014).

  143. 143.

    Felger, J. C. & Treadway, M. T. Inflammation effects on motivation and motor activity: role of dopamine. Neuropsychopharmacology 42, 216–241 (2017). This paper presents a clear account of the links between the immune and DA systems, including how inflammation may result in a decrease in DA transmission, leading to symptoms related to amotivation.

  144. 144.

    Felger, J. C. & Miller, A. H. Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front. Neuroendocrinol. 33, 315–327 (2012).

  145. 145.

    Kapur, S. & Remington, G. Serotonin–dopamine interaction and its relevance to schizophrenia. Am. J. Psychiatry 153, 466–476 (1996).

  146. 146.

    Bailey, M. R. et al. The effects of pharmacological modulation of the serotonin 2C receptor on goal-directed behavior in mice. Psychopharmacology 233, 615–624 (2016).

  147. 147.

    Deakin, J. F. W. & Graeff, F. G. 5-HT and mechanisms of defence. J. Psychopharmacol. 5, 305–315 (1991).

  148. 148.

    Maier, S. F. & Watkins, L. R. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci. Biobehav. Rev. 29, 829–841 (2005).

  149. 149.

    Daw, N. D., Kakade, S. & Dayan, P. Opponent interactions between serotonin and dopamine. Neural Netw. 15, 603–616 (2002).

  150. 150.

    Boureau, Y.-L. & Dayan, P. Opponency revisited: competition and cooperation between dopamine and serotonin. Neuropsychopharmacology 36, 74–97 (2011).

  151. 151.

    Kranz, G. S., Kasper, S. & Lanzenberger, R. Reward and the serotonergic system. Neuroscience 166, 1023–1035 (2010).

  152. 152.

    Nakamura, K., Matsumoto, M. & Hikosaka, O. Reward-dependent modulation of neuronal activity in the primate dorsal raphe nucleus. J. Neurosci. 28, 5331–5343 (2008).

  153. 153.

    Fonseca, M. S., Murakami, M. & Mainen, Z. F. Activation of dorsal raphe serotonergic neurons promotes waiting but is not reinforcing. Curr. Biol. 25, 306–315 (2015).

  154. 154.

    Luo, M., Zhou, J. & Liu, Z. Reward processing by the dorsal raphe nucleus: 5-HT and beyond. Learn. Mem. 22, 452–460 (2015).

  155. 155.

    Faulkner, P. & Deakin, J. F. W. The role of serotonin in reward, punishment and behavioural inhibition in humans: insights from studies with acute tryptophan depletion. Neurosci. Biobehav. Rev. 46, 365–378 (2014).

  156. 156.

    Macoveanu, J. Serotonergic modulation of reward and punishment: evidence from pharmacological fMRI studies. Brain Res. 1556, 19–27 (2014).

  157. 157.

    Seymour, B., Daw, N. D., Roiser, J. P., Dayan, P. & Dolan, R. Serotonin selectively modulates reward value in human decision-making. J. Neurosci. 32, 5833–5842 (2012).

  158. 158.

    Cools, R. et al. Tryptophan depletion disrupts the motivational guidance of goal-directed behavior as a function of trait impulsivity. Neuropsychopharmacology 30, 1362–1373 (2005).

  159. 159.

    Maillet, A. et al. The prominent role of serotonergic degeneration in apathy, anxiety and depression in de novo Parkinson’s disease. Brain 139, 2486–2502 (2016).

  160. 160.

    Da Silva, S. et al. Investigating consummatory and anticipatory pleasure across motivation deficits in schizophrenia and healthy controls. Psychiatry Res. 254, 112–117 (2017).

  161. 161.

    Richards, D. A. et al. Cost and outcome of behavioural activation versus Cognitive Behavioural Therapy for Depression (COBRA): a randomised, controlled, non-inferiority trial. Lancet 388, 871–880 (2016).

  162. 162.

    Lutgens, D., Gariepy, G. & Malla, A. Psychological and psychosocial interventions for negative symptoms in psychosis: systematic review and meta-analysis. Br. J. Psychiatry 210, 324–332 (2017).

  163. 163.

    Rizvi, S. J., Pizzagalli, D. A., Sproule, B. A. & Kennedy, S. H. Assessing anhedonia in depression: potentials and pitfalls. Neurosci. Biobehav. Rev. 65, 21–35 (2016). This is a thorough review of questionnaire, interview and behavioural measurements commonly used to assess anhedonia in humans and behavioural tests assessing related constructs in animals.

  164. 164.

    Strauss, G. P. & Gold, J. M. A. Psychometric comparison of the clinical assessment interview for negative symptoms and the brief negative symptom scale. Schizophr. Bull. 42, 1384–1394 (2016).

  165. 165.

    Kaji, Y. & Hirata, K. Apathy and anhedonia in Parkinson’s disease. ISRN Neurol. 2011, 219427 (2011).

  166. 166.

    Haarasilta, L., Marttunen, M., Kaprio, J. & Aro, H. The 12-month prevalence and characteristics of major depressive episode in a representative nationwide sample of adolescents and young adults. Psychol. Med. 31, 1169–1179 (2001).

  167. 167.

    Keller, M. B. et al. Results of the DSM-IV mood disorders field trial. Am. J. Psychiatry 152, 843–849 (1995).

  168. 168.

    Kiwanuka, J. N., Strauss, G. P., McMahon, R. P. & Gold, J. M. Psychological predictors of functional outcome in people with schizophrenia. Schizophr. Res. 157, 299–304 (2014).

  169. 169.

    Daw, N. D. Decision Making, Affect, and Learning (eds Delgado, M. R., Phelps, E. A. & Robbins, T. W.) 3–38 (Oxford Univ. Press, Oxford, 2011).

  170. 170.

    Anticevic, A. & Murray, J. D. (eds) Computational Psychiatry: Mathematical Modeling of Mental Illness. (Academic Press, Elsevier, London, 2017).

  171. 171.

    Gelman, A. & Shalizi, C. R. Philosophy and the practice of Bayesian statistics. Br. J. Math. Stat. Psychol. 66, 8–38 (2013).

  172. 172.

    Pessiglione, M., Seymour, B., Flandin, G., Dolan, R. J. & Frith, C. D. Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans. Nature 442, 1042–1045 (2006).

  173. 173.

    Sutton, R. S. & Barto, A. G. Reinforcement Learning: An Introduction (MIT Press, Cambridge, 1998).

  174. 174.

    Assadi, S. M., Yücel, M. & Pantelis, C. Dopamine modulates neural networks involved in effort-based decision-making. Neurosci. Biobehav. Rev. 33, 383–393 (2009).

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M.H. and J.P.R. are supported by awards from the Wellcome Trust. M.H. is also supported by the UK National Institute for Health Research (NIHR) Oxford Biomedical Research Centre and the Wellcome Trust Centre for Integrative Neuroimaging, Oxford. J.P.R. is also supported by the Leverhulme Trust.

Reviewer information

Nature Reviews Neuroscience thanks J. Salamone and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information


  1. Nuffield Department of Clinical Neurosciences and Department of Experimental Psychology, University of Oxford. John Radcliffe Hospital, Oxford, UK

    • Masud Husain
  2. Institute of Cognitive Neuroscience, University College London, London, UK

    • Jonathan P. Roiser


  1. Search for Masud Husain in:

  2. Search for Jonathan P. Roiser in:


Both authors researched data for the article, made substantial contributions to discussion of the content, wrote the manuscript and reviewed or edited the manuscript before submission.

Competing interests

M.H. has received an honorarium from Eli Lilly for speaking at their UK annual research symposium in 2017. J.P.R. is a consultant for Cambridge Cognition Ltd, Takeda and GE.

Corresponding author

Correspondence to Masud Husain.



A reason or reasons for acting or behaving in a particular way.

Negative symptoms

Thoughts, feelings or behaviours normally present that are absent or diminished.

DSM-IV field trials

Reports on the first attempts to apply the diagnostic criteria laid down in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition in real-world settings.


Inability to perform self-directed, purposeful activities.


Reduced spontaneous verbal, motor, cognitive and emotional behaviours.

Akinetic mutism

Loss of ability to self-initiate limb movement and speech.


Loss of energy.


Weariness or diminished ability following mental or physical activity.


Approach or goal-seeking phase of behaviour.


Completion or consummation phase of behaviour.


Acquisition of information, in this case to alter future behaviour.


The number of examples generated of a verbal category (for example, words beginning with the letter F) or a non-verbal category (for instance, different patterns on a dot array using four straight lines).

Pavlovian–instrumental transfer

(PIT). The influence of an irrelevant conditioned stimulus on ongoing instrumental behaviour.

Iowa Gambling task

A neuropsychological test of decision making for reward.

Reward responsiveness

The development of a bias towards a more frequently rewarded stimulus.


When a model becomes too complex (has too many parameters) and begins to describe random error in the data rather than the relationships between variables.

Inverse temperature parameter

A constant in the softmax decision rule. It affects the steepness of the function around the inflexion point, resulting in more consistent choices at higher values.

Incremental learning

Learning over trials.

Reward-prediction error

A computational quantity indicating the difference between expected and actual outcomes.

Primary reward

Rewarding stimuli that facilitate survival of an organism or its offspring, such as food, water and sex.

Behavioural activation therapy

A psychological therapy that focuses on activity scheduling to encourage patients to approach activities that they avoid and on analysing processes (for example, rumination) that serve as forms of avoidance.

Cognitive behavioural therapy

A psychological therapy that aims to assist a person to change their thinking and behaviour by practising effective strategies to decrease symptoms and distress.

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