The neuropsychology of ventral prefrontal cortex: Decision-making and reversal learning
Abstract
Converging evidence from human lesion, animal lesion, and human functional neuroimaging studies implicates overlapping neural circuitry in ventral prefrontal cortex in decision-making and reversal learning. The ascending 5-HT and dopamine neurotransmitter systems have a modulatory role in both processes. There is accumulating evidence that measures of decision-making and reversal learning may be useful as functional markers of ventral prefrontal cortex integrity in psychiatric and neurological disorders. Whilst existing measures of decision-making may have superior sensitivity, reversal learning may offer superior selectivity, particularly within prefrontal cortex. Effective decision-making on existing measures requires the ability to adapt behaviour on the basis of changes in emotional significance, and this may underlie the shared neural circuitry with reversal learning.
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Serotonin and striatal dopamine neurotransmitter systems have a modulatory role in reversal learning, as shown by human and animal lesion, stimulation, and neuroimaging studies.
“Serotonin and striatal dopamine neurotransmitter systems have a modulatory role in reversal learning, as evidenced by human and animal lesion, stimulation and neuroimaging studies106.”
From Cognitive and behavioural flexibility: Neural mechanisms and clinical considerations (2021) · cites this paper as [106]
Spatial reversal learning is not exclusively associated with hippocampal function but also with the prefrontal cortex, namely the prelimbic and infralimbic, and orbitalfrontal regions.
“This particular cognitive task is not exclusively associated with hippocampal function but also the prefrontal cortex,42 namely the prelimbic and infralimbic, and orbitalfrontal regions;43”
From Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression (2017) · cites this paper as [42]
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Decision making, impulse control and loss of willpower to resist drugs: a neurocognitive perspective
Bechara, A. (2005) · Nature Neuroscience · doi:10.1038/nn1584 · Cited by 2,149 · see citing works
Menzies, L., Chamberlain, S. R., Laird, A. R., Thelen, S. M., Sahakian, B. J., & Bullmore, E. T. (2008) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2007.09.005 · Cited by 1,190 · see citing works
The Iowa Gambling Task and the somatic marker hypothesis: some questions and answers
Bechara, A., Damasio, H., Tranel, D., & Damasio, A. R. (2005) · Trends in Cognitive Sciences · doi:10.1016/j.tics.2005.02.002 · Cited by 798 · see citing works
Cognitive and behavioural flexibility: Neural mechanisms and clinical considerations
Uddin, L. Q. (2021) · Nature Reviews Neuroscience · doi:10.1038/s41583-021-00428-w · Cited by 698 · see citing works
The neural basis of reversal learning: An updated perspective
Izquierdo, A., Brigman, J. L., Radke, A. K., Rudebeck, P. H., & Holmes, A. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2016.03.021 · Cited by 670 · see citing works
Hongwanishkul, D., Happaney, K. R., Lee, W. S. C., & Zelazo, P. D. (2005) · Developmental Neuropsychology · doi:10.1207/s15326942dn2802_4 · Cited by 654 · see citing works
The prefrontal cortex as a key target of the maladaptive response to stress
Cerqueira, J. J., Mailliet, F., Almeida, O. F. X., Jay, T. M., & Sousa, N. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4372-06.2007 · Cited by 599 · see citing works
Neurochemical Modulation of Response Inhibition and Probabilistic Learning in Humans
Chamberlain, S. R., Müller, U., Blackwell, A. D., Clark, L., Robbins, T. W., & Sahakian, B. J. (2006) · Science · doi:10.1126/science.1121218 · Cited by 573 · see citing works
Self-citationTowards an immuno-precipitated neurodevelopmental animal model of schizophrenia
Meyer, U., Feldon, J., Schedlowski, M., & Yee, B. K. (2005) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2004.10.012 · Cited by 494 · see citing works
Chudasama, Y., & Robbins, T. W. (2006) · Biological Psychology · doi:10.1016/j.biopsycho.2006.01.005 · Cited by 484 · see citing works
Self-citationStress-induced prefrontal reorganization and executive dysfunction in rodents
Holmes, A., & Wellman, C. L. (2009) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2008.11.005 · Cited by 469 · see citing works
Leeman, R. F., & Potenza, M. N. (2012) · Psychopharmacology · doi:10.1007/s00213-011-2550-7 · Cited by 448 · see citing works
Mesocortical dopamine modulation of executive functions: beyond working memory
Floresco, S. B., & Magyar, O. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0404-5 · Cited by 426 · see citing works
Prefrontal mechanisms of behavioral flexibility, emotion regulation and value updating
Rudebeck, P. H., Saunders, R. C., Prescott, A. T., Chau, L. S., & Murray, E. A. (2013) · Nature Neuroscience · doi:10.1038/nn.3440 · Cited by 383 · see citing works
Gläscher, J., Hampton, A. N., & O'Doherty, J. P. (2009) · Cerebral Cortex · doi:10.1093/cercor/bhn098 · Cited by 387 · see citing works
Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder
Remijnse, P. L., Nielen, M. M. A., van Balkom, A. J. L. M., Cath, D. C., van Oppen, P., Uylings, H. B. M., & Veltman, D. J. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.11.1225 · Cited by 408 · see citing works
Rudebeck, P. H., & Murray, E. A. (2014) · Neuron · doi:10.1016/j.neuron.2014.10.049 · Cited by 405 · see citing works
Fettes, P., Schulze, L., & Downar, J. (2017) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2017.00025 · Cited by 299 · see citing works
Amygdala-prefrontal cortical circuitry regulates effort based decision making
Floresco, S. B., & Ghods-Sharifi, S. (2006) · Cerebral Cortex · doi:10.1093/cercor/bhj143 · Cited by 316 · see citing works
Jollant, F., Lawrence, N. S., Olie, E., O'Daly, O., Malafosse, A., Courtet, P., & Phillips, M. L. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.03.027 · Cited by 312 · see citing works
Neural circuits subserving behavioral flexibility and their relevance to schizophrenia
Floresco, S. B., Zhang, Y., & Enomoto, T. (2009) · Behavioural Brain Research · doi:10.1016/j.bbr.2008.12.001 · Cited by 298 · see citing works
Distinguishing whether dopamine regulates liking, wanting, and/or learning about rewards
Robinson, S., Sandstrom, S. M., Denenberg, V. H., & Palmiter, R. D. (2005) · Behavioral Neuroscience · doi:10.1037/0735-7044.119.1.5 · Cited by 247 · see citing works
A neuropsychological comparison of obsessive–compulsive disorder and trichotillomania
Chamberlain, S. R., Fineberg, N. A., Blackwell, A. D., Clark, L., Robbins, T. W., & Sahakian, B. J. (2007) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2006.07.016 · Cited by 212 · see citing works
Self-citationErsche, K. D., Fletcher, P. C., Lewis, S. J. G., Clark, L., Stocks-Gee, G., London, M., Deakin, J. B., Robbins, T. W., & Sahakian, B. J. (2005) · Psychopharmacology · doi:10.1007/s00213-005-2205-7 · Cited by 199 · see citing works
Brigman, J. L., Mathur, P., Harvey-White, J., Izquierdo, A., Saksida, L. M., Bussey, T. J., Fox, S., Deneris, E., Murphy, D. L., & Holmes, A. (2010) · Cerebral Cortex · doi:10.1093/cercor/bhp266 · Cited by 184 · see citing works
Twenty-Five Lessons from Computational Neuromodulation
Dayan, P. (2012) · Neuron · doi:10.1016/j.neuron.2012.09.027 · Cited by 190 · see citing works
Executive functions in decision making: An individual differences approach
Del Missier, F., Mäntylä, T., & Bruine de Bruin, W. (2010) · Thinking & Reasoning · doi:10.1080/13546781003630117 · Cited by 155 · see citing works
Bidirectional modulation of goal-directed actions by prefrontal cortical dopamine
Hitchcott, P. K., Quinn, J. J., & Taylor, J. R. (2007) · Cerebral Cortex · doi:10.1093/cercor/bhm010 · Cited by 143 · see citing works
The neuropsychology of mood disorders
Chamberlain, S. R., & Sahakian, B. J. (2006) · Current Psychiatry Reports · doi:10.1007/s11920-006-0051-x · Cited by 140 · see citing works
Remijnse, P. L., Nielen, M. M. A., van Balkom, A. J. L. M., Hendriks, G.-J., Hoogendijk, W. J., Uylings, H. B. M., & Veltman, D. J. (2009) · Psychological Medicine · doi:10.1017/s0033291708005072 · Cited by 127 · see citing works
A systematic review of impulse control disorders in Parkinson’s disease.
Callesen, M. B., Scheel-Krüger, J., Kringelbach, M. L., & Møller, A. (2013) · Journal of Parkinson s Disease · doi:10.3233/jpd-120165 · Cited by 130 · see citing works
Impaired probabilistic reversal learning in youths with mood and anxiety disorders
Dickstein, D. P., Finger, E. C., Brotman, M. A., Rich, B. A., Pine, D. S., Blair, J. R., & Leibenluft, E. (2010) · Psychological Medicine · doi:10.1017/s0033291709991462 · Cited by 105 · see citing works
“PRR is of particular interest because the circuitry mediating its performance has been well studied in humans and non-human primates (Cools et al. 2002 ; Fellows & Farah, 2003 ; Clark et al. 2004 ; Izquierdo & Murray, 2004 ; Budhani et al. 2007 ; Bellebaum et al. 2008).”
BackgroundInfluentialKetamine modulates fronto-striatal circuitry in depressed and healthy individuals
Mkrtchian, A., Evans, J. W., Kraus, C., Yuan, P., Kadriu, B., Nugent, A. C., Roiser, J. P., & Zarate, C. A. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-00878-1 · Cited by 110 · see citing works
Enge, S., Behnke, A., Fleischhauer, M., Küttler, L., Kliegel, M., & Strobel, A. (2014) · Journal of Experimental Psychology: Learning, Memory, and Cognition · doi:10.1037/a0036165 · Cited by 102 · see citing works
Psychiatric diagnoses and personality traits associated with disadvantageous decision-making
Jollant, F., Guillaume, S., Jaussent, I., Bellivier, F., Leboyer, M., Castelnau, D., Malafosse, A., & Courtet, P. (2007) · European Psychiatry · doi:10.1016/j.eurpsy.2007.06.001 · Cited by 106 · see citing works
The impact of junk foods on the adolescent brain
Reichelt, A. C., & Rank, M. M. (2017) · Birth Defects Research · doi:10.1002/bdr2.1173 · Cited by 102 · see citing works
Adult hippocampal neuroplasticity triggers susceptibility to recurrent depression
Alves, N. D., Correia, J. S., Patrício, P., Mateus-Pinheiro, A., Machado-Santos, A. R., Loureiro-Campos, E., Morais, M., Bessa, J. M., Sousa, N., & Pinto, L. (2017) · Translational Psychiatry · doi:10.1038/tp.2017.29 · Cited by 79 · see citing works
Masaki, D., Yokoyama, C., Kinoshita, S., Tsuchida, H., Nakatomi, Y., Yoshimoto, K., & Fukui, K. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0559-0 · Cited by 73 · see citing works
The potential role of lamotrigine in schizophrenia
Large, C. H., Webster, E. L., & Goff, D. C. (2005) · Psychopharmacology · doi:10.1007/s00213-005-0020-9 · Cited by 69 · see citing works
Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss
Dickson, P. E., Rogers, T. D., Mar, N. D., Martin, L. A., Heck, D., Blaha, C. D., Goldowitz, D., & Mittleman, G. (2010) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2010.05.010 · Cited by 59 · see citing works
Kim, H. W., Kang, J. I., Namkoong, K., Jhung, K., Ha, R. Y., & Kim, S. J. (2015) · Journal of Affective Disorders · doi:10.1016/j.jad.2015.01.060 · Cited by 58 · see citing works
The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study
Alsiö, J., Nilsson, S. R. O., Gastambide, F., Wang, R. A. H., Dam, S. A., Mar, A. C., Tricklebank, M., & Robbins, T. W. (2015) · Psychopharmacology · doi:10.1007/s00213-015-3963-5 · Cited by 53 · see citing works
Self-citationGiner-Bartolomé, C., Fagundo, A. B., Sánchez, I., Jiménez-Murcia, S., Santamaría, J. J., Ladouceur, R., Menchón, J. M., & Fernández-Aranda, F. (2015) · Frontiers in Psychology · doi:10.3389/fpsyg.2015.00982 · Cited by 42 · see citing works
Nicotinic alteration of decision-making
Naudé, J., Dongelmans, M., & Faure, P. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.11.021 · Cited by 39 · see citing works
Intact alternation performance in high lethality suicide attempters
Keilp, J. G., Wyatt, G., Gorlyn, M., Oquendo, M. A., Burke, A. K., & John Mann, J. (2014) · Psychiatry Research · doi:10.1016/j.psychres.2014.04.050 · Cited by 31 · see citing works
Cognitive effects of subdiaphragmatic vagal deafferentation in rats
Klarer, M., Weber-Stadlbauer, U., Arnold, M., Langhans, W., & Meyer, U. (2017) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2017.05.006 · Cited by 25 · see citing works
Granseth, B., Andersson, F. K., & Lindström, S. H. (2015) · Genes, Brain and Behavior · doi:10.1111/gbb.12230 · Cited by 23 · see citing works
Stimulus-reward association and reversal learning in individuals with Asperger Syndrome
Zalla, T., Sav, A.-M., & Leboyer, M. (2009) · Research in Autism Spectrum Disorders · doi:10.1016/j.rasd.2009.03.004 · Cited by 17 · see citing works
Shi, W., Tian, Y., Yang, H., Guo, H., Wen, B., Liu, Z., Zhang, Y., Han, S., & Cheng, J. (2025) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2025.1529983 · Cited by 7 · see citing works
Streur, C. S., Floody, E. A., Lapham, Z. K., & Sandberg, D. E. (2022) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.62564 · Cited by 6 · see citing works
- Authors
- Clark, L., Cools, R., & Robbins, T. W.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Clark, L.
- Venue
- Brain and Cognition
- Publisher
- Elsevier BV
- Published
- 2004-06
- Volume
- 55
- Issue
- 1
- Pages
- 41-53
- ISSN
- 0278-2626 (ISSN-L)
- OpenAlex
- W2160601359
- Cited by
- 439
- References
- 112
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 11 · 2023: 13 · 2022: 13 · 2021: 24 · 2020: 11 · 2019: 15 · 2018: 13 · 2017: 22 · 2016: 23 · 2015: 29 · 2014: 28 · 2013: 35 · 2012: 25
- FWCI
- 2.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain and Cognition (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural and Behavioral Psychology Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Psychology › Clinical Psychology › Historical and Modern Theater Studies
- Keywords
- ventral prefrontal cortex, decision-making, reversal learning, serotonin, dopamine, neural circuits, mental illness, neurological disorders, functional markers, behavioral adaptation
- MeSH terms
- Animals, Brain Damage, Chronic, Brain Mapping, Cognition, Decision Making, Humans, Neuropsychology, Reversal Learning, Serotonin, Tomography, Emission-Computed, Prefrontal Cortex
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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