Abstract
It has been questioned that the more than 300 mental disorders currently listed in international disease classification systems all have a distinct neurobiological correlate. Here, we support the idea that basic dimensions of mental dysfunctions, such as alterations in reinforcement learning, can be identified, which interact with individual vulnerability and psychosocial stress factors and, thus, contribute to syndromes of distress across traditional nosological boundaries. We further suggest that computational modeling of learning behavior can help to identify specific alterations in reinforcement-based decision-making and their associated neurobiological correlates. For example, attribution of salience to drug-related cues associated with dopamine dysfunction in addiction can increase habitual decision-making via promotion of Pavlovian-to-instrumental transfer as indicated by computational modeling of the effect of Pavlovian-conditioned stimuli (here affectively positive or alcohol-related cues) on instrumental approach and avoidance behavior. In schizophrenia, reward prediction errors can be modeled computationally and associated with functional brain activation, thus revealing reduced encoding of such learning signals in the ventral striatum and compensatory activation in the frontal cortex. With respect to negative mood states, it has been shown that both reduced functional activation of the ventral striatum elicited by reward-predicting stimuli and stress-associated activation of the hypothalamic–pituitary–adrenal axis in interaction with reduced serotonin transporter availability and increased amygdala activation by aversive cues contribute to clinical depression; altogether these observations support the notion that basic learning mechanisms, such as Pavlovian and instrumental conditioning and Pavlovian-to-instrumental transfer, represent a basic dimension of mental disorders that can be mechanistically characterized using computational modeling and associated with specific clinical syndromes across established nosological boundaries. Instead of pursuing a narrow focus on single disorders defined by clinical tradition, we suggest that neurobiological research should focus on such basic dimensions, which can be studied in and compared among several mental disorders.
Similar content being viewed by others
References
Adams RA, Stephan KE, Brown HR et al (2013) The computational anatomy of psychosis. Front Psychiatry 4:47. doi:10.3389/fpsyt.2013.00047
Bebko G, Bertocci M, Fournier J et al (2014) Parsing dimensional vs diagnostic category–related patterns of reward circuitry function in behaviorally and emotionally dysregulated youth in the longitudinal assessment of manic symptoms study. JAMA Psychiatry 71:71–80. doi:10.1001/jamapsychiatry.2013.2870
Beck A, Wüstenberg T, Genauck A et al (2012) Effect of brain structure, brain function, and brain connectivity on relapse in alcohol-dependent patients. Arch Gen Psychiatry 69:842–852. doi:10.1001/archgenpsychiatry.2011.2026
Bray S, Rangel A, Shimojo S et al (2008) The neural mechanisms underlying the influence of pavlovian cues on human decision making. J Neurosci 28:5861–5866. doi:10.1523/JNEUROSCI.0897-08.2008
Buckholtz JW, Meyer-Lindenberg A (2012) Psychopathology and the human connectome: toward a transdiagnostic model of risk for mental illness. Neuron 74:990–1004. doi:10.1016/j.neuron.2012.06.002
Burke AR, Miczek KA (2013) Stress in adolescence and drugs of abuse in rodent models: role of dopamine, CRF, and HPA axis. Psychopharmacology 231:1557–1580. doi:10.1007/s00213-013-3369-1
Cardinal RN, Parkinson JA, Marbini HD et al (2003) Role of the anterior cingulate cortex in the control over behavior by Pavlovian conditioned stimuli in rats. Behav Neurosci 117:566–587. doi:10.1037/0735-7044.117.3.566
Caspi A, Sugden K, Moffitt TE et al (2003) Influence of life stress on depression: moderation by a Polymorphism in the 5-HTT Gene. Science 301:386–389. doi:10.1126/science.1083968
Cloninger C (1987) A systematic method for clinical description and classification of personality variants: a proposal. Arch Gen Psychiatry 44:573–588. doi:10.1001/archpsyc.1987.01800180093014
Daw ND, Kakade S, Dayan P (2002) Opponent interactions between serotonin and dopamine. Neural Netw 15:603–616. doi:10.1016/S0893-6080(02)00052-7
Daw ND, Gershman SJ, Seymour B et al (2011) Model-based influences on humans’ choices and striatal prediction errors. Neuron 69:1204–1215. doi:10.1016/j.neuron.2011.02.027
Den Ouden HEM, Daw ND, Fernandez G et al (2013) Dissociable effects of dopamine and serotonin on reversal learning. Neuron 80:1090–1100. doi:10.1016/j.neuron.2013.08.030
Deserno L, Huys QJM, Boehme R et al (2015) Ventral striatal dopamine reflects behavioral and neural signatures of model-based control during sequential decision making. Proc Natl Acad Sci 112:1595–1600. doi:10.1073/pnas.1417219112
Di Chiara G, Bassareo V (2007) Reward system and addiction: what dopamine does and doesn’t do. Curr Opin Pharmacol 7:69–76. doi:10.1016/j.coph.2006.11.003
Dolan RJ, Dayan P (2013) Goals and Habits in the Brain. Neuron 80:312–325. doi:10.1016/j.neuron.2013.09.007
Doll BB, Simon DA, Daw ND (2012) The ubiquity of model-based reinforcement learning. Curr Opin Neurobiol 22:1075–1081. doi:10.1016/j.conb.2012.08.003
Drevets WC, Videen TO, Price JL et al (1992) A functional anatomical study of unipolar depression. J Neurosci 12:3628–3641
Everitt BJ, Robbins TW (2005) Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nat Neurosci 8:1481–1489. doi:10.1038/nn1579
Frances AJ (2013) Saving normal: an insider’s revolt against out-of-control psychiatric diagnosis, DSM-5, big pharma, and the medicalization of ordinary life, 1st edn. William Morrow, New York
Friedel E, Koch SP, Wendt J et al (2014) Devaluation and sequential decisions: linking goal-directed and model-based behavior. Front Hum Neurosci 8:587. doi:10.3389/fnhum.2014.00587
Friston KJ, Stephan KE, Montague R, Dolan RJ (2014) Computational psychiatry: the brain as a phantastic organ. Lancet Psychiatry 1:148–158. doi:10.1016/S2215-0366(14)70275-5
Garbusow M, Schad DJ, Sommer C et al (2014) Pavlovian-to-instrumental transfer in alcohol dependence: a pilot study. Neuropsychobiology 70:111–121. doi:10.1159/000363507
Garbusow M, Schad DJ, Sebold M et al (2015) Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence. Addict Biol. doi:10.1111/adb.12243
Gillan CM, Robbins TW (2014) Goal-directed learning and obsessive-compulsive disorder. Philos Trans R Soc Lond B Biol Sci. doi:10.1098/rstb.2013.0475
Grüsser SM, Wrase J, Klein S et al (2004) Cue-induced activation of the striatum and medial prefrontal cortex is associated with subsequent relapse in abstinent alcoholics. Psychopharmacology 175:296–302. doi:10.1007/s00213-004-1828-4
Hägele C, Schlagenhauf F, Rapp M et al (2014) Dimensional psychiatry: reward dysfunction and depressive mood across psychiatric disorders. Psychopharmacology 232:331–341. doi:10.1007/s00213-014-3662-7
Hariri AR, Mattay VS, Tessitore A et al (2002) Serotonin transporter genetic variation and the response of the human amygdala. Science 297:400–403. doi:10.1126/science.1071829
Heinz A (2002) Dopaminergic dysfunction in alcoholism and schizophrenia—psychopathological and behavioral correlates. Eur Psychiatry 17:9–16. doi:10.1016/S0924-9338(02)00628-4
Heinz A, Dufeu P, Kuhn S et al (1996) Psychopathological and behavioral correlates of dopaminergic sensitivity in alcohol-dependent patients. Arch Gen Psychiatry 53:1123–1128. doi:10.1001/archpsyc.1996.01830120061011
Heinz A, Higley JD, Gorey JG et al (1998) In vivo association between alcohol intoxication, aggression, and serotonin transporter availability in nonhuman primates. Am J Psychiatry 155:1023–1028
Heinz A, Jones DW, Mazzanti C et al (2000) A relationship between serotonin transporter genotype and in vivo protein expression and alcohol neurotoxicity. Biol Psychiatry 47:643–649. doi:10.1016/S0006-3223(99)00171-7
Heinz A, Mann K, Weinberger DR, Goldman D (2001) Serotonergic dysfunction, negative mood states, and response to alcohol. Alcohol Clin Exp Res 25:487–495. doi:10.1111/j.1530-0277.2001.tb02240.x
Heinz A, Jones DW, Bissette G et al (2002) Relationship between cortisol and serotonin metabolites and transporters in alcolholism. Pharmacopsychiatry 35:127–134. doi:10.1055/s-2002-33197
Heinz A, Löber S, Georgi A et al (2003) Reward craving and withdrawal relief craving: assessment of different motivational pathways to alcohol intake. Alcohol Alcohol 38:35–39. doi:10.1093/alcalc/agg005
Heinz A, Siessmeier T, Wrase J et al (2004) Correlation between dopamine D(2) receptors in the ventral striatum and central processing of alcohol cues and craving. Am J Psychiatry 161:1783–1789. doi:10.1176/appi.ajp.161.10.1783
Heinz A, Braus DF, Smolka MN et al (2005a) Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci 8:20–21. doi:10.1038/nn1366
Heinz A, Siessmeier T, Wrase J et al (2005b) Correlation of alcohol craving with striatal dopamine synthesis capacity and D2/3 receptor availability: a combined [18F]DOPA and [18F]DMFP PET study in detoxified alcoholic patients. Am J Psychiatry 162:1515–1520. doi:10.1176/appi.ajp.162.8.1515
Heinz AJ, Beck A, Meyer-Lindenberg A et al (2011) Cognitive and neurobiological mechanisms of alcohol-related aggression. Nat Rev Neurosci 12:400–413. doi:10.1038/nrn3042
Heinz A, Deserno L, Reininghaus U (2013) Urbanicity, social adversity and psychosis. World Psychiatry 12:187–197. doi:10.1002/wps.20056
Heinz A, Friedel E, Krüger H-P, Wackerhagen C (2015) Philosophical implications of changes in the classification of mental disorders in DSM-5. Springer, Netherlands
Higley J, Thompson W, Champoux M et al (1993) Paternal and maternal genetic and environmental contributions to cerebrospinal fluid monoaminemetabolites in rhesus monkeys (macaca mulatta). Arch Gen Psychiatry 50:615–623. doi:10.1001/archpsyc.1993.01820200025003
Higley JD, Suomi SJ, Linnoila M (1996a) A nonhuman primate model of type II alcoholism? Part 2. Diminished social competence and excessive aggression correlates with low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations. Alcohol Clin Exp Res 20:643–650
Higley JD, Suomi SJ, Linnoila M (1996b) A nonhuman primate model of type II excessive alcohol consumption? Part 1. Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and diminished social competence correlate with excessive alcohol consumption. Alcohol Clin Exp Res 20:629–642. doi:10.1111/j.1530-0277.1996.tb01665.x
Holsboer F (1988) Implications of altered limbic-hypothalamic-pituitary-adrenocortical (LHPA)-function for neurobiology of depression. Acta Psychiatr Scand Suppl 341:72–111
Holsboer F (2000) The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 23:477–501. doi:10.1016/S0893-133X(00)00159-7
Howes O, Kambeitz J, Kim E et al (2012) The nature of dopamine dysfunction in schizophrenia and what this means for treatment: meta-analysis of imaging studies. Arch Gen Psychiatry 69:776–786. doi:10.1001/archgenpsychiatry.2012.169
Huys QJM, Cools R, Gölzer M et al (2011) Disentangling the roles of approach, activation and valence in instrumental and pavlovian responding. PLoS Comput Biol 7:e1002028. doi:10.1371/journal.pcbi.1002028
Huys QJM, Gölzer M, Friedel E et al (2016) The specificity of Pavlovian regulation is associated with recovery from depression. Psychol Med 46:1027–1035. doi:10.1017/S0033291715002597
Igbal N, van Praag HM (1995) The role of serotonin in schizophrenia. Eur Neuropsychopharmacol 5. Supplement 1:11–23. doi:10.1016/0924-977X(95)00027-M
Insel T, Cuthbert B, Garvey M et al (2010) Research domain criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 167:748–751. doi:10.1176/appi.ajp.2010.09091379
Jaspers K (1946) Allgemeine Psychopathologie. Ein Leitfaden für Studierende, Ärzte und Psychologen, 4th edn. Springer, Berlin
Juckel G, Schlagenhauf F, Koslowski M et al (2006) Dysfunction of ventral striatal reward prediction in schizophrenia. NeuroImage 29:409–416. doi:10.1016/j.neuroimage.2005.07.051
Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160:13–23. doi:10.1176/appi.ajp.160.1.13
Kienast T, Hariri AR, Schlagenhauf F et al (2008) Dopamine in amygdala gates limbic processing of aversive stimuli in humans. Nat Neurosci 11:1381–1382. doi:10.1038/nn.2222
Knutson B, Westdorp A, Kaiser E, Hommer D (2000) FMRI visualization of brain activity during a monetary incentive delay task. NeuroImage 12:20–27. doi:10.1006/nimg.2000.0593
Knutson B, Adams CM, Fong GW, Hommer D (2001) Anticipation of increasing monetary reward selectively recruits nucleus accumbens. J Neurosci 21:RC159–RC159
Kobiella A, Reimold M, Ulshöfer DE et al (2011) How the serotonin transporter 5-HTTLPR polymorphism influences amygdala function: the roles of in vivo serotonin transporter expression and amygdala structure. Transl Psychiatry 1:e37. doi:10.1038/tp.2011.29
Kumakura Y, Cumming P, Vernaleken I et al (2007) Elevated [18F]fluorodopamine turnover in brain of patients with schizophrenia: an [18F]fluorodopa/positron emission tomography study. J Neurosci 27:8080–8087. doi:10.1523/JNEUROSCI.0805-07.2007
Lesch K-P, Bengel D, Heils A et al (1996) Association of Anxiety-Related Traits with a polymorphism in the serotonin transporter gene regulatory region. Sci Novemb 29(274):1527–1531
Martinez D, Gil R, Slifstein M et al (2005) Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry 58:779–786. doi:10.1016/j.biopsych.2005.04.044
Montague PR, Hyman SE, Cohen JD (2004) Computational roles for dopamine in behavioural control. Nature 431:760–767. doi:10.1038/nature03015
Nemeroff CB (1989) Clinical significance of psychoneuroendocrinology in psychiatry: focus on the thyroid and adrenal. J Clin Psychiatry 50(Suppl):13–20 (discussion 21–22)
O’brien CP, Childress AR, McLellan AT, Ehrman R (1992) Classical conditioning in drug-dependent humans. Ann NY Acad Sci 654:400–415. doi:10.1111/j.1749-6632.1992.tb25984.x
Ohlmeier MD, Peters K, Wildt BTT et al (2008) Comorbidity of alcohol and substance dependence with attention-deficit/hyperactivity disorder (ADHD). Alcohol Alcohol 43:300–304. doi:10.1093/alcalc/agn014
Otto AR, Raio CM, Chiang A et al (2013) Working-memory capacity protects model-based learning from stress. Proc Natl Acad Sci USA 110:20941–20946. doi:10.1073/pnas.1312011110
Pankow A, Friedel E, Sterzer P et al (2013) Altered amygdala activation in schizophrenia patients during emotion processing. Schizophr Res 150:101–106. doi:10.1016/j.schres.2013.07.015
Park SQ, Kahnt T, Beck A et al (2010) Prefrontal Cortex Fails to Learn from Reward Prediction Errors in Alcohol Dependence. J Neurosci Off J Soc Neurosci 30:7749–7753. doi:10.1523/JNEUROSCI.5587-09.2010
Parsey RV, Hastings RS, Oquendo MA et al (2006) Effect of a triallelic functional polymorphism of the serotonin-transporter-linked promoter region on expression of serotonin transporter in the human brain. Am J Psychiatry 163:48–51. doi:10.1176/appi.ajp.163.1.48
Radenbach C, Reiter AMF, Engert V et al (2015) The interaction of acute and chronic stress impairs model-based behavioral control. Psychoneuroendocrinology 53:268–280. doi:10.1016/j.psyneuen.2014.12.017
Rapp MA, Kluge U, Penka S et al (2015) When local poverty is more important than your income: mental health in minorities in inner cities. World Psychiatry 14:249–250. doi:10.1002/wps.20221
Reimold M, Knobel A, Rapp MA et al (2011) Central serotonin transporter levels are associated with stress hormone response and anxiety. Psychopharmacology 213:563–572. doi:10.1007/s00213-010-1903-y
Robinson T, Berridge KC (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev 18:247–291. doi:10.1016/0165-0173(93)90013-P
Russell JA, Weiss A, Mendelsohn GA (1989) Affect Grid: A single-item scale of pleasure and arousal. J Personality Soc Psychol 57:493. doi:10.1037/0022-3514.57.3.493
Schlagenhauf F, Sterzer P, Schmack K et al (2009) Reward feedback alterations in unmedicated schizophrenia patients: relevance for delusions. Biol Psychiatry 65:1032–1039. doi:10.1016/j.biopsych.2008.12.016
Schlagenhauf F, Rapp MA, Huys QJM et al (2013) Ventral striatal prediction error signaling is associated with dopamine synthesis capacity and fluid intelligence. Hum Brain Mapp 34:1490–1499. doi:10.1002/hbm.22000
Schlagenhauf F, Huys QJM, Deserno L et al (2014) Striatal dysfunction during reversal learning in unmedicated schizophrenia patients. NeuroImage 89:171–180. doi:10.1016/j.neuroimage.2013.11.034
Schultz W, Apicella P, Ljungberg T (1993) Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task. J Neurosci 13:900–913
Schultz W, Dayan P, Montague PR (1997) A neural substrate of prediction and reward. Science 275:1593–1599. doi:10.1126/science.275.5306.1593
Sebold M, Deserno L, Nebe S et al (2014) Model-based and model-free decisions in alcohol dependence. Neuropsychobiology 70:122–131. doi:10.1159/000362840
Spanagel R, Durstewitz D, Hansson A, et al (2013) A systems medicine research approach for studying alcohol addiction Addict Biol 18:883–896. doi:10.1111/adb.12109
Thome J, Weijers HG, Wiesbeck GA et al (1999) Dopamine D3 receptor gene polymorphism and alcohol dependence: relation to personality rating. Psychiatr Genet 9:17–21
Tiffany ST (1990) A cognitive model of drug urges and drug-use behavior: role of automatic and nonautomatic processes. Psychol Rev 97:147–168. doi:10.1037/0033-295X.97.2.147
van Praag HM, Asnis GM, Kahn RS et al (1990) Monoamines and abnormal behaviour. A multi-aminergic perspective. Br J Psychiatry 157:723–734. doi:10.1192/bjp.157.5.723
Voon V, Derbyshire K, Rück C et al (2015) Disorders of compulsivity: a common bias towards learning habits. Mol Psychiatry 20:345–352. doi:10.1038/mp.2014.44
Watson D, Clark LA (1984) Negative affectivity: the disposition to experience aversive emotional states. Psychol Bull 96:465–490. doi:10.1037/0033-2909.96.3.465
Watson D, Tellegen A (1985) Toward a consensual structure of mood. Psychol Bull 98:219–235. doi:10.1037/0033-2909.98.2.219
Watson D, Clark LA, Tellegen A (1988) Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 54:1063–1070. doi:10.1037/0022-3514.54.6.1063
Wiers RW, Rinck M, Kordts R et al (2010) Retraining automatic action-tendencies to approach alcohol in hazardous drinkers. Addiction 105:279–287. doi:10.1111/j.1360-0443.2009.02775.x
Wiers RW, Eberl C, Rinck M et al (2011) Retraining automatic action tendencies changes alcoholic patients’ approach bias for alcohol and improves treatment outcome. Psychol Sci 22:490–497. doi:10.1177/0956797611400615
Wiers CE, Stelzel C, Gladwin TE et al (2014a) Effects of cognitive bias modification training on neural alcohol cue reactivity in alcohol dependence. Am J Psychiatry 172:335–343. doi:10.1176/appi.ajp.2014.13111495
Wiers CE, Stelzel C, Park SQ et al (2014b) Neural correlates of alcohol-approach bias in alcohol addiction: the spirit is willing but the flesh is weak for spirits. Neuropsychopharmacology 39:688–697. doi:10.1038/npp.2013.252
Wrase J, Schlagenhauf F, Kienast T et al (2007) Dysfunction of reward processing correlates with alcohol craving in detoxified alcoholics. NeuroImage 35:787–794. doi:10.1016/j.neuroimage.2006.11.043
Acknowledgments
This work was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft: DFG FOR 1617 and Excellence Cluster Exc 257) as well as by the Bundesministerium für Bildung und Forschung (project ‘e:Med Alcohol Addiction—A Systems Oriented Approach’ (Spanagel et al. 2013); Grant 01ZX1311D and 01ZX1311E; and in part by 01EE1406A as well as project ‘Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders), Grant 01ZX1314B).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Heinz, A., Schlagenhauf, F., Beck, A. et al. Dimensional psychiatry: mental disorders as dysfunctions of basic learning mechanisms. J Neural Transm 123, 809–821 (2016). https://doi.org/10.1007/s00702-016-1561-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-016-1561-2