In the current issue of Biological Psychiatry: Global Open Science, Kesby et al. (
1
) provide one of the most comprehensive overviews on the neural circuitry of salience and reward processing in psychosis. Based on their thought-provoking synthesis, the authors put forward an important argument: that salience and reward processing dysfunction seen in psychosis originates in the subcortical regions, with cortical abnormalities arising only later in established stages of schizophrenia. They also list several cortical areas (the orbitofrontal, ventromedial, and dorsolateral prefrontal cortices and the ventral and superior frontal and dorsal anterior cingulate cortices) as having distinct roles in representing salience, reward processing, and the precision of prediction error signals.SEE CORRESPONDING ARTICLE ON PAGE 33
First, their interesting hypothesis of subcortico-cortical progression is built on reports of excess striatal dopamine synthesis capacity in early at-risk stages of illness, defined by the presence of subthreshold positive symptoms. In this regard, it is important to note that more recent meta-analytical evidence is less convincing of striatal hyperdopaminergia in at-risk subjects (
2
). In fact, the effect size of the reported presynaptic dopamine excess in clinical high-risk individuals has decreased over time since the work that Kesby et al. (1
) cite in favor of this argument was published (3
). While this can be attributed to reduced transition rates, indicating a reduction in the number of subjects with “early stage of schizophrenia” in recent cohorts, meta-analysis of variance does not support the presence of higher interindividual variation that may occur if subgroups with hyperdopaminergic profile were present (2
). The genetic high-risk groups also fail to show elevated striatal dopamine synthesis capacity (2
).A recent study comprised entirely of antipsychotic drug–naïve patients with first-episode psychosis failed to reveal an excess of dopamine synthesis capacity despite the relatively limited duration of untreated psychosis (
4
). Nevertheless, in this study, patients with higher positive symptom burden at baseline had higher dopamine synthesis capacity. Similarly, in patients with more established illness, reduced striatal dopamine synthesis capacity is associated with more prominent negative symptoms (- Sigvard A.K.
- Nielsen M.Ø.
- Gjedde A.
- Bojesen K.B.
- Fuglø D.
- Tangmose K.
- et al.
Dopaminergic activity in antipsychotic-naïve patients assessed with positron emission tomography before and after partial dopamine D2 receptor agonist treatment: Association with psychotic symptoms and treatment response.
Biol Psychiatry. 2022; 91: 236-245
5
). Taken together, we can expect a subtype of patients with more insidious onset with less prominent positive symptoms but more negative symptoms to have no striatal hyperdopaminergia on presentation but instead have a “cortical origin schizophrenia.” In other words, the sequence of anatomical changes describing disease progression may not be the same across all subjects. This possibility needs to be considered in future longitudinal studies that empirically test the hypothesis of subcortical origin of salience processing deficits.Second, of the several cortical areas listed as key components of salience and prediction error processing in psychosis, there is an intriguing absence of the anterior insula. The anterior insula is seen as the seat of a cortical salience processing system, often termed the salience network (
6
). One of the most replicated structural observations in schizophrenia is the bilateral reduction of gray matter in the anterior insular cortex (7
). Of direct relevance to their synthesis of prediction error literature, a recent meta-analysis cited by Kesby et al. (1
) indeed highlights the striatum and insula as the two core regions tracking domain-general prediction error signals (8
).The unusual overweighting of perceptual priors seen as a crucial feature of hallucinations relates to anterior insular activity (
9
). Limongi et al. (10
) originally hypothesized a role for the anterior insula in overweighting priors to compensate for aberrant precision weighting of prediction errors in psychosis and found empirical evidence from drift-diffusion modeling of Stroop task performance in patients with first-episode psychosis in support (11
). Thus, aberrant striatal dopamine signaling in psychosis, via inappropriate weighting of prediction error signals (i.e., excess precision afforded to discrete perceptual events), may propagate hierarchically to the anterior insula, generating the response of overweighted priors. But this kind of cortical response is unlikely to be a late-in-the-illness effect, as experimental manipulation of dopamine levels results in immediately observable changes in how cortical salience processing regions track beliefs about the environment (12
). Furthermore, overweighting of priors appear to have a role in hallucinations (13
), which, if any, are less prominent in late than in earlier stages of schizophrenia (14
).The subcortical dopamine dysfunction and cortical information processing deficits are likely to be two component parts of a pathophysiological continuum. While we currently do not know which of these two appear first in the course of this illness, the full spectrum of clinical expression may necessitate some degree of concomitant disruption in both component parts.
Acknowledgments and Disclosures
The author acknowledges salary support from the Tanna Schulich Chair of Neuroscience and Mental Health.
The author reports personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; and investigator-initiated educational grants from Janssen Canada, Sunovion Canada, and Otsuka Canada outside the submitted work.
References
- Neural circuitry of salience and reward processing in psychosis.Biol Psychiatry Glob Open Sci. 2023; 3: 33-46
- Dopamine and glutamate in individuals at high risk for psychosis: A meta-analysis of in vivo imaging findings and their variability compared to controls.World Psychiatry. 2021; 20: 405-416
- Dopamine synthesis capacity before onset of psychosis: A prospective [18F]-DOPA PET imaging study.Am J Psychiatry. 2011; 168: 1311-1317
- Dopaminergic activity in antipsychotic-naïve patients assessed with positron emission tomography before and after partial dopamine D2 receptor agonist treatment: Association with psychotic symptoms and treatment response.Biol Psychiatry. 2022; 91: 236-245
- Clinical correlation but no elevation of striatal dopamine synthesis capacity in two independent cohorts of medication-free individuals with schizophrenia.Mol Psychiatry. 2022; 27: 1241-1247
- Does the salience network play a cardinal role in psychosis? An emerging hypothesis of insular dysfunction.J Psychiatry Neurosci. 2012; 37: 17-27
- Systematic meta-analysis of insula volume in schizophrenia.Biol Psychiatry. 2012; 72: 775-784
- Meta-analysis of human prediction error for incentives, perception, cognition, and action.Neuropsychopharmacology. 2022; 47: 1339-1349
- Pavlovian conditioning-induced hallucinations result from overweighting of perceptual priors.Science. 2017; 357: 596-600
- Knowing when to stop: Aberrant precision and evidence accumulation in schizophrenia.Schizophr Res. 2018; 197: 386-391
- Glutamate and dysconnection in the salience network: Neurochemical, effective connectivity, and computational evidence in schizophrenia.Biol Psychiatry. 2020; 88: 273-281
- Dopaminergic modulation of the exploration/exploitation trade-off in human decision-making.Elife. 2020; 9e51260
- Hallucinations and strong priors.Trends Cogn Sci. 2019; 23: 114-127
- The 10-year trajectories of auditory hallucinations among 496 patients with a first schizophrenia-spectrum disorder: Findings from the OPUS cohort.Schizophr Res. 2022; 243: 385-391
Article info
Publication history
Published online: January 10, 2022
Accepted:
December 24,
2021
Received:
December 22,
2021
Identification
Copyright
© 2022 THE AUTHOR. Published by Elsevier Inc on behalf of the Society of Biological Psychiatry.
User license
Creative Commons Attribution (CC BY 4.0) | How you can reuse 
Elsevier's open access license policy
Creative Commons Attribution (CC BY 4.0)
Permitted
- Read, print & download
- Redistribute or republish the final article
- Text & data mine
- Translate the article
- Reuse portions or extracts from the article in other works
- Sell or re-use for commercial purposes
Elsevier's open access license policy
ScienceDirect
Access this article on ScienceDirectLinked Article
- Neural Circuitry of Salience and Reward Processing in PsychosisBiological Psychiatry: Global Open ScienceVol. 3Issue 1
- PreviewThe processing of salient and rewarding stimuli is integral to engaging our attention, stimulating anticipation for future events, and driving goal-directed behaviors. Widespread impairments in these processes are observed in psychosis, which may be associated with worse functional outcomes or mechanistically linked to the development of symptoms. Here, we summarize the current knowledge of behavioral and functional neuroimaging in salience, prediction error, and reward. Although each is a specific process, they are situated in multiple feedback and feedforward systems integral to decision making and cognition more generally.
- Full-Text
- Preview
