Changing the Antipsychotic in Early Nonimprovers to Amisulpride or Olanzapine: Randomized, Double-Blind Trial in Patients With Schizophrenia, Natural Language Processing: Its Potential Role in Clinical Care and Clinical Research, Jumping to Conclusions and Its Associations With Psychotic Experiences in Preadolescent Children at Familial High Risk of Schizophrenia or Bipolar Disorder-The Danish High Risk and Resilience Study, VIA 11, Efficacy of Transcranial Direct Current Stimulation to Improve Insight in Patients With Schizophrenia: A Systematic Review and Meta-analysis of Randomized Controlled Trials, About the University of Maryland School of Medicine, About the Maryland Psychiatric Research Center, Receive exclusive offers and updates from Oxford Academic, Impaired Activation in Cognitive Control Regions Predicts Reversal Learning in Schizophrenia, Motivational Context Modulates Prediction Error Response in Schizophrenia, Striatal Presynaptic Dopamine in Schizophrenia, Part I: Meta-Analysis of Dopamine Active Transporter (DAT) Density, Dopaminergic Function in the Psychosis Spectrum: An [. Within the UHR group, in a multiple regression model including the CAARMS thought content subscale together with each of the PANSS subscales, which was significant overall [F(4,11) = 3.77, P = .036], both the thought content subscale (t = 2.9, P = .016) and the PANNS positive subscale (t = 2.3, P = .042) were significant predictors of ventral striatal responses to irrelevant cue features. Cropsey PD

Roiser There was a significant group ventral striatal 18F-DOPA Ki interaction for adaptive reward prediction responses in a large cluster comprising ventrolateral bilateral occipital gyri, right inferior temporal gyrus, right medial PFC, right supramarginal gyrus, and the planum temporale (Z = 4.32; PWBC < .001 [cluster level]; online supplementary figure 3A). den Ouden The first 4 images in each series were discarded to allow for signal stabilization. S (a & b) The magnitude of aberrant salience attribution was positively correlated with ventral striatal response to irrelevant cue features (peak voxel: [x = 12; y = 18; z = 12]), with a significantly steeper slope [F(1,31) = 9.39, P = .004] in controls (r = .74, P < .001 [uncorrected]) than UHR subjects (r = .40, P = .11 [uncorrected]). In the right ventral striatum, there was a trend toward responses being positively associated with SAT explicit adaptive salience, but this did not approach significance following Bonferroni correction for the 3 ROIs (Z = 3.31, PSVCB = .19, PSVC = .069; online supplementary figure 2B).

Murray P Shaner . (1) Bilateral striatum: 15-mm-radius spheres centered on maxima from our previous study (right [x = 12; y = 12; z = 3]; left [x = 12; y = 9; z = 3]). Values indicate means (standard deviations). Do patients with schizophrenia exhibit aberrant salience?

A model including each of the CAARMS subscales showed a trend toward significance overall [F(3,12) = 3.46, P = .051], but none of the individual subscales approached significance. West A Two contrast images were generated per participant, representing (1) adaptive reward prediction and (2) aberrant reward prediction.

Thus, in healthy volunteers, reward anticipation elicits activation in the striatum, hippocampus, and PFC, as well as striatal dopamine release.12 There is also evidence that motivational salience processing13,14 and associated neural responses1519 are perturbed in psychotic patients. EPI data were analyzed with Statistical Parametric Mapping (SPM5: www.fil.ion.ucl.ac.uk/spm) in the context of the general linear model (GLM).24 EPIs were initially realigned, spatially normalized, and smoothed before being entered into a GLM that included the 4 cue regressors, an outcome regressor, and its parametric modulation by reward magnitude. In other words, the impact of high dopamine synthesis capacity on motivational salience signaling may depend on the baseline state of the dopamine system, modulated by ventral hippocampus activity.

Howes

Sheehan Moreover, elevated striatal dopamine synthesis capacity is evident in individuals with prodromal signs of psychosis,9 especially those who subsequently develop psychosis,10 and may increase during the transition to psychosis.11, The same regions implicated in aberrant motivational salience processing in experimental animals also participate in adaptive (appropriate) motivational salience processing in humans. G The contrast of primary interest was aberrant reward prediction: This yields differential neural responses between cue features that the participant erroneously indicated (through VAS ratings) were different predictors of reward. Fletcher

Kraft et al. Moreover, the adaptive reward prediction contrast did not differentiate the groups even at a very liberal threshold. It is unlikely that these effects reflect some general cognitive deficit, because the SAT incorporates a positive control, the adaptive (appropriate) salience contrast, which did not differentiate the groups at either the behavioral or the neural level. den Ouden For post hoc analyses of group interactions, we report uncorrected P values for illustrative purposes (indicated by the suffix uncorrected).

HE Mechelli SB For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Two experimental sessions (64 trials each) were performed during fMRI. Data from experimental animals suggest that aberrant motivational salience attribution results from out-of-context dopamine signaling in the ventral striatum,2,3 which may in turn be driven by abnormal regulation of subcortical dopamine transmission by the prefrontal cortex (PFC)5 and hippocampus.6,7 This is consistent with robust evidence of abnormal dopamine transmission in psychotic patients, as indexed by increased striatal dopamine synthesis and release,8 though, interestingly, the most reliable effects have been identified in the dorsal, not the ventral, striatum. Wittmann SK Maldjian RA Romaniuk . hardy paranoia garety philippa kcl preprint Collectively, our findings are consistent with several predictions of the aberrant salience model of psychosis.2 At the behavioral level, UHR individuals scored higher on the SAT explicit aberrant salience measure than controls. AA Moreover, ventral striatal responses to irrelevant cue features correlated positively with the severity of positive symptoms in the UHR subjects (figure 2C). Grace

et al. This represented a subset of subjects included in our previous study.10 All participants were right-handed native English speakers and free of antipsychotic medication at the time of scanning. From drugs to deprivation: a Bayesian framework for understanding models of psychosis, Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia, Divergent activation of ventromedial and ventrolateral dopamine systems in animal models of amphetamine sensitization and schizophrenia, Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging, Elevated striatal dopamine function linked to prodromal signs of schizophrenia, Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study, Progressive increase in striatal dopamine synthesis capacity as patients develop psychosis: a PET study, Mesolimbic functional magnetic resonance imaging activations during reward anticipation correlate with reward-related ventral striatal dopamine release.

The UHR group additionally showed increased right DLPFC responses to stimulus features that were erroneously inferred to be poorer predictors of reward, though this finding did not survive stringent Bonferroni correction for multiple ROIs and, therefore, this result should be treated with caution until independently replicated. D Striatal dopamine synthesis capacity correlated negatively with hippocampal responses to irrelevant stimulus features in ultra-high risk individuals, but this relationship was positive in controls. However, we consider that this is unlikely to have affected the results, because none of the behavioral and neuroimaging measures reflecting adaptive motivational salience differed significantly between the groups. A Individuals at ultra-high risk of psychosis were more likely to attribute motivational salience to irrelevant stimulus features (t(26.7) = 2.8, P = .008), and this bias was related to the severity of their delusion-like symptoms (r = .62, P = .008). J We defined 3 regions of interest (ROIs) for our fMRI analyses. .

EM

N Urban However, the opposite relationship applied in the UHR group (r = .52, P = .035 [uncorrected]; figure 3B). F Behavioral data. Flandin Tamminga Robinson However, the slope of the regression line was significantly flatter and nonsignificant in UHR subjects (explicit aberrant salience group interaction: F(1,31) = 9.39, P = .004; figure 2B). RB et al. Schmack Across all subjects, presentation of high-probability, relative to low-probability, cue features elicited responses in the ventral striatum (right: Z = 5.60, PSVC< .001, PSVCB< .001; left: Z = 5.92, PSVC < .001, PSVCB< .001; online supplementary figure 2A). Fiszbein Lahti CA Thompson Fourth, we did not measure socioeconomic state in our study, raising the possibility that the subjective value of the monetary incentives we provided may have differed between the groups. Pessiglione For completeness, for all analyses, we list all clusters at the P < .005 (uncorrected), 30-contiguous-voxel threshold in online supplementary tables 14. First, the small sample in which we were able to acquire both PET and fMRI data limits the generalizability of our findings and the sensitivity of our analyses. AA In contrast to the correlation with explicit aberrant salience, this relationship was similar in the 2 groups (explicit adaptive salience group interaction: F(1,31) < 1; online supplementary figure 2C). There was no evidence for this in either group (controls: mean RT difference = 3.1ms, SD = 31.5ms, t < 1; UHR: mean RT difference = 3.7ms, SD = 21.5ms, t < 1). This is consistent with the putative role of the ventral striatum in the aberrant salience model2 and in the pathophysiology of psychosis more generally. This may have accounted for the absence of significant group differences in striatal dopamine synthesis capacity.9 With 18 subjects in each group, we had only 59% power to detect an effect size of .75 between the groups, as reported in our previous study.9 Hence, for this comparison, which our study was not designed to address, the chance of Type II error was relatively high. KL et al. This is thought to occur during the prodromal phase of psychotic disorders, but this prediction has not been tested previously. HP . The probability of reward varied along one of the cue dimensions (task-relevant dimension, eg, colorblue stimuli: 87.5% rewarded; red stimuli: 12.5% rewarded), but not for the other (task-irrelevant dimension, eg, formanimal and household stimuli: both 50% rewarded). OD McGorry Seymour Mild hypothermia fails to protect infant macaques from brain injury caused by prolonged exposure to Antiseizure drugs. et al. AC A similar interaction was evident in the motor cortex (left: Z = 4.42, PWBC < .001 [cluster level]; right: Z = 4.13, PWBC = .006 [cluster level]) and in the left occipital/parietal cortex, although in the latter region, the differential relationship was with dopamine synthesis capacity in the ventral striatum (Z = 4.28, PWBC = .002 [cluster level]). CL RT measures were square-root transformed prior to analysis to reduce skew. Pantelis

R Howes Acquisition of reward contingencies was assessed using a 1-sample t test against 0 on the SAT adaptive salience measures. et al.

et al. Dolan S-ketamine Administration in Pregnant Mice Induces ADHD- and Depression-like behaviors in Offspring Mice. However, most previous studies included patients treated with antipsychotic medication, which blocks dopamine transmission and may thereby attenuate normal motivational salience processing, complicating the interpretation of these results.2,20 Although 2 studies reported attenuated reward-related striatal responses in unmedicated psychotic patients,18,21 this abnormality was related to negativeand not positivesymptoms, a pattern also described in medicated patients.22,23. EM Asselin KJ . Howes Detailed methods are provided in the online supplementary material. The peak in the right caudate was selected for post hoc analysis (see online supplementary figure 3).

HE Finally, our study only assessed motivational salience; beyond the scope of the present investigation, it would be interesting to determine whether other aspects of salience processing (eg, novelty, perceptual abnormalities) operate abnormally in UHR individuals. Burdette Turkheimer

L B

Weiler Lodge Clark . GK BH

Barnes Mirroring the behavioral results, there were no group differences in adaptive (appropriate) reward prediction responses, even at a very liberal threshold (see online supplementary table 1). In UHR individuals, in whom inappropriate dopamine firing may occur more frequently, high dopamine synthesis capacity might impair the transmission of appropriate motivational salience signals, equally potentiating inappropriate signals. . BC The nature of this relationship in UHR subjects was opposite to that observed in controls, though this interaction only showed a trend toward significance following stringent Bonferroni correction for multiple ROIs and should therefore be interpreted with caution. Wechsler Stephan MC Slifstein

Medical Research Council (U.1200.04.007.00001.01); the Biomedical Research Centre, Kings College London. Future studies should examine the relationship between phasic dopamine transmissioneg, that measured using 11C-raclopride displacementand motivational salience processing in individuals at risk for psychosis.33. Yung HH PR DR Ultra-high risk (UHR) individuals exhibited (a) elevated explicit aberrant salience but (b) equivalent explicit adaptive salience relative to controls. The groups did not differ on any measure of dopamine synthesis capacity, in either the whole striatum or its subregions (t < 1 for all regions). S PC Similar interactions were also evident in the left putamen/thalamus extending to the parietal cortex (Z = 3.55, PWBC = .036 [cluster level]) and the right caudate/inferior frontal gyrus (Z=3.84, PWBC = .024 [cluster level]). UHR individuals scored significantly higher than controls on SAT explicit aberrant salience [t(26.7) = 2.8, P = .008; figure 1A; table 1], indicating a greater tendency to rate 1 irrelevant cue feature as more associated with reward than the other. P Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. Oxford University Press is a department of the University of Oxford. . Dzel Juckel We corrected for multiple comparisons, controlling the family-wise error adjusted for small volume (PSVC) across each of our ROIs at the voxel level. Across all subjects, there was a positive relationship between aberrant reward prediction responses in the ventral striatum and SAT explicit aberrant salience (Z =4.08, PSVCB = .018, PSVC = .006; figure 2A). Velakoulis Copyright 2022 Maryland Psychiatric Research Center and Oxford University Press. The authors have declared that there are no conflicts of interest in relation to the subject of this study. In UHR subjects, SAT explicit aberrant salience showed a particular association with the severity of abnormal beliefs. Waltz SB Allan Further analyses confirmed that the CAARMS thought content scale was correlated with ventral striatal responses (r = .59, P = .017; figure 2C). A Koslowski Murray Miller KJ

The groups did not differ on SAT explicit adaptive salience [t(34) = 1.0, P = .32; figure 1B; table 1], indicating that the ability of UHR individuals to discriminate between high- and low-probability cue features was unimpaired. There was a trend for a group difference on SAT implicit adaptive salience [t(34) = 1.74, P = .091], but both groups responded significantly faster on high-probability, relative to low-probability, trials [controls: t(17) = 3.58, P = .002; UHR: t(17) = 2.28, P = .036; table 1]. M All UHR individuals confirmed having experienced attenuated psychotic symptoms, and the majority scored at least 3 (moderate severity) on the CAARMS thought content (delusion-like symptoms) or perceptual abnormalities (hallucination-like symptoms) scales at the time of testing. One possible explanation relates to the role that the ventral hippocampus plays in regulating phasic and tonic (baseline) dopamine neuron firing, via a circuit including pallidal gamma aminobutyric acidsecreting projections to the ventral tegmental area (VTA). A Tamminga

Berridge Stephan GD Kapur Stokes

. Either of these effects of heightened dopamine system responsivity could conceivably be exacerbated in UHR individuals with high dopamine synthesis capacity, because each action potential would be expected to release proportionately more dopamine. Importantly, excluding these 2 participants did not change the results. et al. JR (a & b) In controls, aberrant reward prediction signals in the hippocampus (peak voxel: [x = 33; y = 36; z = 9]) correlated positively with 18F-DOPA Ki in the dorsal striatum (r = .65, P = .004 [uncorrected]), but the same relationship was negative in UHR individuals (r = .52, P = .035 [uncorrected]). The SAT provides measures of adaptive (relevant) and aberrant (irrelevant) motivational salience on the basis of visual analogue scale ratings (VAS: explicit salience) and reaction times (RTs: implicit salience; see online supplementary methods). These data are consistent with the hypothesis that aberrant salience processing underlies psychotic symptoms and involves functional alterations in the striatum, hippocampus, and the subcortical dopamine system. et al. Motivational saliencerelated responses were assessed using the Salience Attribution Test (SAT),13,24 which features both relevant and irrelevant stimuli, during functional magnetic resonance imaging (fMRI). ): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10, The positive and negative syndrome scale (PANSS) for schizophrenia, National Adult Reading Test (NART): Test Manual, Wechsler Abbreviated Scale of Intelligence, An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets, No adjustments are needed for multiple comparisons, Three-dimensional maximum probability atlas of the human brain, with particular reference to the temporal lobe, Striatal dopamine release in schizophrenia comorbid with substance dependence [published online ahead of print August 7, 2012], Anticipation of novelty recruits reward system and hippocampus while promoting recollection, Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons, Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and longitudinal MRI comparison, Altered medial temporal activation related to local glutamate levels in subjects with prodromal signs of psychosis, The hippocampus modulates dopamine neuron responsivity by regulating the intensity of phasic neuron activation, Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission, Probing the human hippocampus using rCBF: contrasts in schizophrenia, Modulation of limbic circuitry predicts treatment response to antipsychotic medication: a functional imaging study in schizophrenia.

Moore Behavioral data were analyzed using the Statistical Package for the Social Sciences (SPSS 16: SPSS Inc., Chicago, IL). Nelson KC L

Ethical approval was obtained from the LondonHarrow Research Ethics Committee. PR In the present study, we tested this model in 18 healthy volunteers and 18 unmedicated individuals at ultra-high risk of psychosis. Instead, we speculate that the weaker relationship between ventral striatal response and aberrant motivational salience in UHR subjects may reflect inconsistent phasic (ie, stimulus-evoked) dopamine signaling related to stimuli whose association with reward is relatively uncertain (see also the following paragraphs). In healthy volunteers, high dopamine synthesis capacity may facilitate the transmission of motivational salience, potentiating appropriate phasic signals against a background of relatively low gain or tonic dopamine release. Yuen Allom This tendency was correlated with the severity of their abnormal beliefs, as were the ventral striatal responses to stimulus features inappropriately assigned motivational salience. Jensen Howes Corlett Ash . Y Opler . . However, we were unable to confirm all aspects of the aberrant salience hypothesis: Presynaptic dopamine synthesis capacity did not differ significantly between UHR subjects and controls in this sample; and no group differences in neural responses during aberrant reward prediction survived stringent correction for multiple comparisons. McGorry It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. PJ Gold However, the aberrant salience model posits that it is the response to irrelevant stimuli that is critically disrupted in psychosis2 and that this drives the emergence of psychotic symptoms during the prodrome. Additionally, though not predicted by the aberrant salience hypothesis, we identified several striking opposite relationships in the 2 groups in terms of the relationship between presynaptic dopamine synthesis capacity and motivational salience-related neural responses, both adaptive and aberrant. Corlett PD

KE . King C E Note: M, Male; F, Female; UHR, Ultra-high risk for psychosis; IQ, Intelligence quotient; NART, National Adult Reading Test; CAARMS, Comprehensive Assessment of At-Risk Mental State, scored from 0 (no symptom) to 6 (psychotic level of symptom); PANSS, Positive and Negative Syndrome Scale; SAT, Salience Attribution Test; VAS, Visual Analogue Scale. PR Ventral striatal responses to irrelevant stimulus features were also correlated with delusion-like symptoms in the ultra-high risk group (r = .59, P = .017). Valli In controls, there was a positive correlation between the hippocampal response to irrelevant cue features and striatal dopamine synthesis capacity (r = .65, P = .004 [uncorrected]). Two UHR subjects had developed a first episode of psychosis between presentation and scanning and had received antipsychotic medication, but they had been unmedicated for at least 6 months by the time of scanning. Full fMRI results are presented in the online supplementary tables 14. This region was chosen on the basis of the hypothesized role of the right DLPFC in psychosis16 and our earlier study.24 (3) Bilateral hippocampus: defined using the Automated Anatomical Labeling Atlas.30 This region was chosen on the basis of the hypothesized role for the hippocampus in psychosis through its regulation of dopamine signaling, as suggested by the methylazoxymethanol acetate (MAM) model of psychosis,6 and prior work indicating a relationship between dopamine and motivational salience processing in this region.12 Note that the ROI definitions for the fMRI analyses differ from those used for the PET analyses: The latter were performed on individual participants, whereas the former were applied to group-averaged voxel maps. HH In a multiple regression model including the CAARMS thought content subscale together with each of the PANSS subscales (positive, negative, general), which was significant overall [F(4,12) = 4.66, P = .017], only the thought content subscale was a significant predictor of SAT explicit aberrant salience (t = 2.2, P = .048). Turkheimer The contingencies between category and reward probability were counterbalanced across participants and remained constant throughout the task. . Our primary prediction was that symptomatic UHR individuals would show aberrant motivational salience behaviorally, as previously described in first-episode psychosis.13 We also tested the prediction that aberrant motivational salience processing would be associated with altered activation in the striatum, PFC and hippocampus, and with the level of subcortical dopamine synthesis capacity. JP K Relationships between neural responses and behavior on the SAT and dopamine synthesis capacity were identified by including parameters from the SAT and18F-DOPA PET analyses as covariates. M Institute of Cognitive Neuroscience, University College London. Minuzzi GD The Author 2012. Dolan Contemporary models of psychosis13 propose that the development of psychotic symptoms, such as delusions, is driven by the inappropriate processing of stimuli that would normally be considered irrelevant, due to aberrant salience.2 In the context of this model, salience refers to the motivational properties of a stimulus, which can cause it to attract attention and drive behavior.4 Aberrant salience refers to the tendency for irrelevant stimuli to be attributed motivational salience and thus to attract attention and influence behavior inappropriately. Nonetheless, it is consistent with other work that found that patients with psychosis inappropriately engage the right PFC during the processing of irrelevant stimuli.16, The attenuated relationship between ventral striatal responses and aberrant motivational salience in the UHR group is unlikely to reflect a generalized blunting in this region, because the relationship between ventral striatal responses and adaptive motivational salience in UHR subjects was very similar to that in controls.