Abstract
The aberrant salience hypothesis proposes that striatal dopamine dysregulation causes
misattribution of salience to irrelevant stimuli leading to psychosis. Recently, new
lines of preclinical evidence on information coding by subcortical dopamine coupled
with computational models of the brain’s ability to predict and make inferences about
the world (predictive processing) provide a new perspective on this hypothesis. We
review these and summarize the evidence for dopamine dysfunction, reward processing,
and salience abnormalities in people at clinical high risk of psychosis (CHR) relative
to findings in patients with psychosis. This review identifies consistent evidence
for dysregulated subcortical dopamine function in people at CHR, but also indicates
a number of areas where neurobiological processes are different in CHR subjects relative
to patients with psychosis, particularly in reward processing. We then consider how
predictive processing models may explain psychotic symptoms in terms of alterations
in prediction error and precision signaling using Bayesian approaches. We also review
the potential role of environmental risk factors, particularly early adverse life
experiences, in influencing the prior expectations that individuals have about their
world in terms of computational models of the progression from being at CHR to frank
psychosis. We identify a number of key outstanding questions, including the relative
roles of prediction error or precision signaling in the development of symptoms and
the mechanism underlying dopamine dysfunction. Finally, we discuss how the integration
of computational psychiatry with biological investigation may inform the treatment
for people at CHR of psychosis.
Keywords
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References
- Striatonigrostriatal pathways in primates form an ascending spiral from the shell to the dorsolateral striatum.J Neurosci. 2000; 20: 2369-2382
- A neural substrate of prediction and reward.Adv Sci. 1997; 275: 1593-1599
- Temporal difference models describe higher-order learning in humans.Nature. 2004; 429: 664-667
- Importance of unpredictability for reward responses in primate dopamine neurons.J Neurophysiol. 1994; 72: 1024-1027
- Responses of monkey dopamine neurons during learning of behavioral reactions.J Neurophysiol. 1992; 67: 145-163
- An electrophysiological characterization of ventral tegmental area dopaminergic neurons during differential pavlovian fear conditioning in the awake rabbit.Behav Brain Res. 1999; 99: 169-179
- Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans.Nature. 2006; 442: 1042-1045
- Midbrain dopaminergic neurons and striatal cholinergic interneurons encode the difference between reward and aversive events at different epochs of probabilistic classical conditioning trials.J Neurosci. 2008; 28: 11673-11684
- Restraint increases dopaminergic burst firing in awake rats.Neuropsychopharmacology. 2005; 30: 1832-1840
- Phasic excitation of dopamine neurons in ventral VTA by noxious stimuli.Proc Natl Acad Sci U S A. 2009; 106: 4894-4899
- Dopamine in motivational control: Rewarding, aversive, and alerting.Neuron. 2010; 68: 815-834
- Real-time assessments of dopamine function during behavior: Single-unit recording, iontophoresis, and fast-scan cyclic voltammetry in awake, unrestrained rats.Alcohol Clin Exp Res. 1998; 22: 32
- Mesocortical and mesostriatal dopamine responses to salient non-rewards events.Neuroscience. 2000; 96: 651-656
- Dopamine reward prediction-error signalling: A two-component response.Nat Rev Neurosci. 2016; 17: 183-195
- Dopaminergic basis for signaling belief updates, but not surprise, and the link to paranoia.Proc Natl Acad Sci U S A. 2018; 115: E10167-E10176
- Knowing how much you don’t know: A neural organization of uncertainty estimates.Nat Rev Neurosci. 2012; 13: 572-586
- Dopamine, reward learning, and active inference.Front Comput Neurosci. 2015; 9: 1-16
- The anatomy of choice: Dopamine and decision-making.Philos Trans R Soc B Biol Sci. 2014; 369: 20130481
- Dopaminergic medication increases reliance on current information in Parkinson’s disease.Nat Hum Behav. 2017; 1: 1-18
- Dopamine neurons code subjective sensory experience and uncertainty of perceptual decisions.Proc Natl Acad Sci U S A. 2011; 108: 19767-19771
- Midbrain dopamine neurons signal belief in choice accuracy during a perceptual decision.Curr Biol. 2017; 27: 821-832
- Review. Explicit neural signals reflecting reward uncertainty.Philos Trans R Soc Lond B Biol Sci. 2008; 363: 3801-3811
- Tamping ramping: Algorithmic, implementational, and computational explanations of phasic dopamine signals in the accumbens.PLoS Comput Biol. 2015; 11: 1-34
- Ramping and state uncertainty in the dopamine signal.bioRxiv. 2019; https://doi.org/10.1101/805366
- Ramping and phasic dopamine activity accounts for efficient cognitive resource allocation during reinforcement learning.bioRxiv. 2019; https://doi.org/10.1101/381103
- Dopamine, inference, and uncertainty.Neural Comput. 2017; 29: 3311-3326
- Adaptive prediction error coding in the human midbrain and striatum facilitates behavioral adaptation and learning efficiency.Neuron. 2016; 90: 1127-1138
- The computational anatomy of psychosis.Front Psychiatry. 2013; 4: 1-26
- Disrupted prediction-error signal in psychosis: Evidence for an associative account of delusions.Brain. 2007; 130: 2387-2400
- The formation of abnormal associations in schizophrenia: Neural and behavioral evidence.Neuropsychopharmacology. 2008; 33: 473-479
- Midbrain activation during pavlovian conditioning and delusional symptoms in schizophrenia.Arch Gen Psychiatry. 2010; 67: 1246
- Dysfunction of ventral striatal reward prediction in schizophrenia.Neuroimage. 2006; 29: 409-416
- Reward feedback alterations in unmedicated schizophrenia patients: Relevance for delusions.Biol Psychiatry. 2009; 65: 1032-1039
- Patients with schizophrenia have a reduced neural response to both unpredictable and predictable primary reinforcers.Neuropsychopharmacology. 2009; 34: 1567-1577
- Salience network-midbrain dysconnectivity and blunted reward signals in schizophrenia.Psychiatry Res Neuroimaging. 2013; 211: 104-111
- Substantia nigra/ventral tegmental reward prediction error disruption in psychosis.Mol Psychiatry. 2008; 13: 267-276
- Abnormal responses to monetary outcomes in cortex, but not in the basal ganglia, in schizophrenia.Neuropsychopharmacology. 2010; 35: 2427-2439
- Aberrant effective connectivity in schizophrenia patients during appetitive conditioning.Front Hum Neurosci. 2011; 4: 1-14
- Modeling subjective relevance in schizophrenia and its relation to aberrant salience.PLoS Comput Biol. 2018; 14: 1-23
- Disambiguating ventral striatum fMRI-related bold signal during reward prediction in schizophrenia.Mol Psychiatry. 2012; 17: 280-289
- Alterations of the brain reward system in antipsychotic nave schizophrenia patients.Biol Psychiatry. 2012; 71: 898-905
- Dysfunction of ventral striatal reward prediction in schizophrenic patients treated with typical, not atypical, neuroleptics.Psychopharmacology (Berl). 2006; 187: 222-228
- Functional imaging of the human dopaminergic midbrain.Trends Neurosci. 2009; 32: 321-328
- The nature of dopamine dysfunction in schizophrenia and what this means for treatment.Arch Gen Psychiatry. 2012; 69: 776-786
- Nigral stress-induced dopamine release in clinical high risk and antipsychotic-naïve schizophrenia.Schizophr Bull. 2018; 44: 542-551
- Increased stress-induced dopamine release in psychosis.Biol Psychiatry. 2012; 71: 561-567
- Baseline and amphetamine-stimulated dopamine activity are related in drug-naïve schizophrenic subjects.Biol Psychiatry. 2009; 65: 1091-1093
- Midbrain dopamine function in schizophrenia and depression: A post-mortem and positron emission tomographic imaging study.Brain. 2013; 136: 3242-3251
- Defining the locus of dopaminergic dysfunction in schizophrenia: A meta-analysis and test of the mesolimbic hypothesis.Schizophr Bull. 2018; 44: 1301-1311
- Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.Arch Gen Psychiatry. 2010; 67: 231
- Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.Proc Natl Acad Sci U S A. 2000; 97: 8104-8109
- Striatal amphetamine-induced dopamine release in patients with schizotypal personality disorder studied with single photon emission computed tomography and [123I]iodobenzamide.Biol Psychiatry. 2004; 55: 1001-1006
- Elevated dopa decarboxylase activity in living brain of patients with psychosis.Proc Natl Acad Sci U S A. 1994; 91: 11651-11654
- A test of the transdiagnostic dopamine hypothesis of psychosis using positron emission tomographic imaging in bipolar affective disorder and schizophrenia.JAMA Psychiatry. 2017; 74: 1206-1213
- Dopamine neuron systems in the brain: An update.Trends Neurosci. 2007; 30: 194-202
- Schizophrenia, dopamine and the striatum: From biology to symptoms.Trends Neurosci. 2019; 42: 205-220
- Elevated striatal dopamine function linked to prodromal signs of schizophrenia.Arch Gen Psychiatry. 2009; 66: 13-20
- Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: A PET study.Mol Psychiatry. 2011; 16: 885-886
- Presynaptic striatal dopamine dysfunction in people at ultra-high risk for psychosis: Findings in a second cohort.Biol Psychiatry. 2013; 74: 106-112
- Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at ultra high risk for psychosis.Eur Neuropsychopharmacol. 2012; 23: 126-132
- Dopamine D2 and D3 binding in people at clinical high risk for schizophrenia, antipsychotic-naive patients and healthy controls while performing a cognitive tasks.J Psychiatry Neurosci. 2013; 38: 98-106
- Abnormal frontostriatal interactions in people with prodromal signs of psychosis: A multimodal imaging study.Arch Gen Psychiatry. 2010; 67: 683-691
- Dopamine synthesis capacity before onset of psychosis: A prospective [18F]-DOPA PET imaging study.Am J Psychiatry. 2011; 168: 1311-1317
- Schizotypy trait and striatal dopamine receptors in healthy volunteers.Psychiatry Res Neuroimaging. 2012; 201: 218-221
- Correlation of individual differences in schizotypal personality traits with amphetamine-induced dopamine release in striatal and extrastriatal brain regions.Am J Psychiatry. 2011; 168: 418-426
- Stress-induced dopamine response in subjects at clinical high risk for schizophrenia with and without concurrent cannabis use.Neuropsychopharmacology. 2014; 39: 1479-1489
- Determinants of treatment response in first-episode psychosis: An 18 F-DOPA PET study.Mol Psychiatry. 2019; 24: 1502-1512
- Schizophrenia: An integrated sociodevelopmental-cognitive model.Lancet. 2014; 383: 1677-1687
- An integrative perspective on the role of dopamine in schizophrenia.Biol Psychiatry. 2016; 81: 52-66
- Prediction error, ketamine and psychosis: An updated model.J Psychopharmacol. 2016; 30: 1145-1155
- Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia.Am J Psychiatry. 2003; 160: 13-23
- Dopaminergic dysfunction in alcoholism and schizophrenia—psychopathological and behavioral correlates.Eur Psychiatry. 2002; 17: 9-16
- What is the role of dopamine in reward: Hedonic impact, reward learning, or incentive salience?.Brain Res Rev. 1998; 28: 309-369
- Ventral striatal activation during reward processing in psychosis: A neurofunctional meta-analysis.JAMA Psychiatry. 2015; 72: 1243-1251
- Ventral striatal activation during reward processing in subjects with ultra-high risk for schizophrenia.Neuropsychobiology. 2012; 66: 50-56
- Symptom dimensions are associated with reward processing in unmedicated persons at risk for psychosis.Front Behav Neurosci. 2014; 8: 382
- Altered activation and connectivity in a hippocampal-basal ganglia-midbrain circuit during salience processing in subjects at ultra high risk for psychosis [published correction appears in Transl Psychiatry 2018; 8:170].Transl Psychiatry. 2017; 7: e1245
- Evidence of reward system dysfunction in youth at clinical high-risk for psychosis from two event-related fMRI paradigms.Schizophr Res. 2019; ([published online ahead of print Apr 15])
- Abnormal reward prediction-error signalling in antipsychotic naive individuals with first-episode psychosis or clinical risk for psychosis.Neuropsychopharmacology. 2018; 43: 1691-1699
- Longitudinal alterations in motivational salience processing in ultra-high-risk subjects for psychosis.Psychol Med. 2017; 47: 243-254
- Modulation of motivational salience processing during the early stages of psychosis.Schizophr Res. 2015; 166: 17-23
- Neural and behavioral correlates of aberrant salience in individuals at risk for psychosis.Schizophr Bull. 2013; 39: 1328-1336
- Neural circuitry of novelty salience processing in psychosis risk: Association with clinical outcome.Schizophr Bull. 2020; 46: 670-679
- Ventral striatal dysfunction and symptom expression in individuals with schizotypal personality traits and early psychosis.Schizophr Bull. 2018; 44: 147-157
- Polygenic risk of psychosis and ventral striatal activation during reward processing in healthy adolescents.JAMA Psychiatry. 2016; 73: 852-861
- The predictive coding account of psychosis.Biol Psychiatry. 2018; 84: 634-643
- The free-energy principle: a rough guide to the brain?.Trends Cogn Sci. 2009; 13: 293-301
- From drugs to deprivation: A Bayesian framework for understanding models of psychosis.Psychopharmacology (Berl). 2009; 206: 515-530
- Computational psychiatry: The brain as a phantastic organ.Lancet Psychiatry. 2014; 1: 148-158
- Thought insertion as a self-disturbance: An integration of predictive coding and phenomenological approaches.Front Hum Neurosci. 2016; 10: 502
- Phenomenology is Bayesian in its application to delusions.World Psychiatry. 2015; 14: 184-185
- Decision-making in schizophrenia: A predictive-coding perspective.Neuroimage. 2019; 190: 133-143
- Attention, uncertainty, and free-energy.Front Hum Neurosci. 2010; 4: 215
- Hallucinations and strong priors.Trends Cogn Sci. 2019; 23: 114-127
- Introducing a Bayesian model of selective attention based on active inference.Sci Rep. 2019; 9: 1-22
- Atypical scanpaths in schizophrenia: Evidence of a trait- or state-dependent phenomenon?.J Psychiatry Neurosci. 2011; 36: 150-164
- A perceptual inference mechanism for hallucinations linked to striatal dopamine.Curr Biol. 2018; 28: 503-514
- Pavlovian conditioning–induced hallucinations result from overweighting of perceptual priors.Science. 2017; 357: 596-600
- When Broca goes uninformed: Reduced information flow to Broca’s area in schizophrenia patients with auditory hallucinations.Schizophr Bull. 2013; 39: 1087-1095
- Deficits in predictive coding underlie hallucinations in schizophrenia.J Neurosci. 2014; 34: 8072-8082
- Dopaminergic dysfunction in schizophrenia: Salience attribution revisited.Schizophr Bull. 2010; 36: 472-485
- Linking unfounded beliefs to genetic dopamine availability.Front Hum Neurosci. 2015; 9: 521
- The neurobiology of schizotypy: Fronto-striatal prediction error signal correlates with delusion-like beliefs in healthy people.Neuropsychologia. 2012; 50: 3612-3620
- The social defeat hypothesis of schizophrenia: An update.Schizophr Bull. 2013; 39: 1180-1186
- The dopamine hypothesis of schizophrenia: Version III—the final common pathway.Schizophr Bull. 2009; 35: 549-562
- Schizophrenic delusions in Seoul, Shanghai and Taipei: A transcultural study.J Korean Med Sci. 2001; 16: 88-94
- The role of genes, stress, and dopamine in the development of schizophrenia.Biol Psychiatry. 2017; 81: 9-20
- Adversity and psychosis: A 10-year prospective study investigating synergism between early and recent adversity in psychosis.Acta Psychiatr Scand. 2012; 125: 388-399
- Does population density and neighborhood deprivation predict schizophrenia? A nationwide Swedish family-based study of 2.4 million individuals.Schizophr Bull. 2015; 41: 494-502
- Schizophrenia and migration: A meta-analysis and review.Am J Psychiatry. 2005; 162: 12-24
- Schizophrenia and urbanicity: A major environmental influence—conditional on genetic risk.Schizophr Bull. 2005; 31: 795-799
- Childhood adversities increase the risk of psychosis: A meta-analysis of patient-control, prospective-and cross-sectional cohort studies.Schizophr Bull. 2012; 38: 661-671
- A neurobiological hypothesis for the classification of schizophrenia: Type A (hyperdopaminergic) and type B (normodopaminergic).Br J Psychiatry. 2014; 205: 1-3
- Stress sensitivity, aberrant salience, and threat anticipation in early psychosis: An experience sampling study.Schizophr Bull. 2016; 42: 712-722
- Blunted cortisol awakening response in people at ultra high risk of developing psychosis.Schizophr Res. 2014; 158: 25-31
- Cortisol awakening response and diurnal cortisol among children at elevated risk for schizophrenia: Relationship to psychosocial stress and cognition.Psychoneuroendocrinology. 2014; 46: 1-13
- Cortisol levels and risk for psychosis: Initial findings from the North American Prodrome Longitudinal Study.Biol Psychiatry. 2013; 74: 410-417
- Association of amphetamine-induced striatal dopamine release and cortisol responses to psychological stress.Neuropsychopharmacology. 2007; 32: 2310-2320
- Effects of acute metabolic stress on the dopaminergic and pituitary–adrenal axis activity in patients with schizophrenia, their unaffected siblings and controls.Schizophr Res. 2008; 100: 206-211
- The stress cascade and schizophrenia: Etiology and onset.Schizophr Bull. 2003; 29: 671-692
- Elevated striatal dopamine function in immigrants and their children: A risk mechanism for psychosis.Schizophr Bull. 2017; 43: 293-301
- Adversity in childhood linked to elevated striatal dopamine function in adulthood.Schizophr Res. 2016; 176: 171-176
- Differential effect of stress on in vivo dopamine release in striatum, nucleus accumbens, and medial frontal cortex.J Neurochem. 1989; 52: 1655-1658
- Modeling sensitization to stimulants in humans: An [11C]raclopride/positron emission tomography study in healthy men.Arch Gen Psychiatry. 2006; 63: 1386-1395
Nestler EJ, Human SE, Malenka RC (2014): Widely projecting systems: Monoamines, acetylcholine, and orexin. In: Sydor A, Brown RY, editors. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience, 3rd ed. New York: McGraw-Hill, pp 147–148, 154–157.
- Salience representation in the parietal and frontal cortex.J Cogn Neurosci. 2010; 22: 918-930
- From prediction error to psychosis: Ketamine as a pharmacological model of delusions.J Psychopharmacol. 2007; 21: 238-252
- Frontal responses during learning predict vulnerability to the psychotogenic effects of ketamine: Linking cognition, brain activity, and psychosis.Arch Gen Psychiatry. 2006; 63: 611-621
- Delusions and the role of beliefs in perceptual inference.J Neurosci. 2013; 33: 13701-13712
- Enhanced predictive signalling in schizophrenia.Hum Brain Mapp. 2017; 38: 1767-1779
- 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
- Deficits in prefrontal cortical and extrastriatal dopamine release in schizophrenia.JAMA Psychiatry. 2015; 72: 316-324
- Impaired prefrontal cortical dopamine release in schizophrenia during a cognitive task: A [11C]FLB 457 positron emission tomography study.Schizophr Bull. 2018; 45: 670-679
- Schizophrenia—an overview.JAMA Psychiatry. 2019; ([published online ahead of print Oct 30])
- Prefrontal cortical dopamine release in clinical high risk for psychosis during a cognitive task: A [11C]FLB457 positron emission tomography study.Eur Neuropsychopharmacol. 2019; 29: 1023-1032
- Developmental pathology, dopamine, stress and schizophrenia.Int J Dev Neurosci. 2011; 29: 207-213
- Dopamine supports coupling of attention-related networks.J Neurosci. 2012; 32: 9582-9587
- Disruption of anterior insula modulation of large-scale brain networks in schizophrenia.Biol Psychiatry. 2013; 74: 467-474
- Inflammation and the neural diathesis-stress hypothesis of schizophrenia: A reconceptualization.Transl Psychiatry. 2017; 7e1024
- The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: A cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study.Lancet Psychiatry. 2018; 5: 816-823
- Efficacy and acceptability of interventions for attenuated positive psychotic symptoms in individuals at clinical high risk of psychosis: A network meta-analysis.Front Psychiatry. 2018; 9: 187
- Lack of evidence to favor specific preventive interventions in psychosis: A network meta-analysis.World Psychiatry. 2018; 17: 196-209
- Preventing a first episode of psychosis: Meta-analysis of randomized controlled prevention trials of 12 month and longer-term follow-ups.Schizophr Res. 2013; 149: 56-62
- Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology.Neuropharmacology. 2019; 9: 107704
- Discrete coding of reward probability and uncertainty by dopamine neurons.Science. 2003; 299: 1898-1902
Article info
Publication history
Published online: March 31, 2020
Accepted:
March 10,
2020
Received in revised form:
March 10,
2020
Received:
August 1,
2019
Identification
Copyright
© 2020 Society of Biological Psychiatry.
