Institute of Cognitive Neuroscience, University College London, London, UK, Wellcome Trust Centre for Neuroimaging, London, UK, Imperial College Faculty of Medicine, Department of Psychological Medicine, Imperial College London, Charing Cross Site, London, UK, https://doi.org/10.1017/S0033291708003863, Reference Laruelle, Abi-Dargham, van Dyck, Gil, DSouza, Erdos, McCance, Rosenblatt, Fingado, Zoghbi, Baldwin, Seibyl, Krystal, Charney and Innis, Reference Abi-Dargham, Rodenhiser, Printz, Zea-Ponce, Gil, Kegeles, Weiss, Cooper, Mann, Van Heertum, Gorman and Laruelle, Reference McGowan, Lawrence, Sales, Quested and Grasby, Reference Waltz, Frank, Robinson and Gold, Reference Juckel, Schlagenhauf, Koslowski, Wustenberg, Villringer, Knutson, Wrase and Heinz, Reference Jensen, Willeit, Zipursky, Savina, Smith, Menon, Crawley and Kapur, Reference Chapman, Chapman, Kwapil, Eckblad and Zinser, Reference Stefanis, Van Os, Avramopoulos, Smyrnis, Evdokimidis, Hantoumi and Stefanis, Reference Joyce, Hutton, Mutsatsa and Barnes, Reference Jablensky, Sartorius, Ernberg, Anker, Korten, Cooper, Day and Bertelsen, Reference Jablensky, McGrath, Herrman, Castle, Gureje, Evans, Carr, Morgan, Korten and Harvey, Reference Addington, Addington and Schissel, Reference Young, Biggs, Ziegler and Meyer, Reference Sheehan, Lecrubier, Sheehan, Amorim, Janavs, Weiller, Hergueta, Baker and Dunbar, Reference Pessiglione, Seymour, Flandin, Dolan and Frith, Reference Seymour, Daw, Dayan, Singer and Dolan, Reference Hietala, Syvalahti, Vuorio, Rakkolainen, Bergman, Haaparanta, Solin, Kuoppamaki, Kirvela and Ruotsalainen, Reference Murray, Corlett, Clark, Pessiglione, Blackwell, Honey, Jones, Bullmore, Robbins and Fletcher, Reference Taylor, Phan, Britton and Liberzon, Reference Knutson, Bjork, Fong, Hommer, Mattay and Weinberger, Do we still believe in the dopamine hypothesis? Therefore aberrant salience was always positive, whereas adaptive salience could be positive or negative. On reinforced trials where participants responded before the probe disappeared, but slower than their mean RT, the message Hitgood: 10 pence was displayed. * Patients exhibited reduced adaptive salience relative to controls (p=0.002). However, there was no difference in VAS aberrant salience between patients with hallucinations [n=9, mean SAPS global hallucinations score 3.9 (s.d.=1.4)] and those without (n=11) (t=1.3, p=0.21, Cohen's d=0.6). Therefore, these results should be treated with caution until replicated. If participants responded prematurely (<100ms after the onset of the probe), the message displayed was Too early: 5 pence. RT and VAS aberrant salience scores from the SAT were square root-transformed prior to analysis to reduce skew, though untransformed values are presented in the text, figures and tables for clarity. After a variable period of time (between 0.5 and 1.5s) the probe appeared and participants attempted to respond before it disappeared. Biases in performance on a probabilistic inference task, Stimulus differentiation by schizophrenic and normal subjects under conditions of reward and punishment, Patients with schizophrenia demonstrate dissociation between affective experience and motivated behavior, Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients, Psychotic disorders in urban areas: an overview of the Study on Low Prevalence Disorders, Australian and New Zealand Journal of Psychiatry, Schizophrenia: manifestations, incidence and course in different cultures. Joyce, Eileen M. For digit-span, stage (forwards/backwards for digit-span) was the within-subjects variable, while on the SAT block (1/2) was the within-subjects variable. Contemporary accounts of reward learning suggest that phasic dopamine firing codes reward prediction errors (Schultz et al. Corlett, P.R. Roiser, Jonathan P. We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Lees, Andrew J The other dimension, in this example shape, was task-irrelevant, so that 16 out of 32 (50%) of both levels were reinforced. 5). Participants were not informed of these contingencies, but instead learned them over the course of the game. Lee, Sooyeon Bonnemann, Catharina Fletcher, P.C. 2). Reference Pessiglione, Seymour, Flandin, Dolan and Frith2006). "isUnsiloEnabled": true, For example, functional neuroimaging studies have shown dopamine dysregulation in both medicated and unmedicated patients (Hietala et al. Reference Waltz, Frank, Robinson and Gold2007; Jensen et al. Gonzalez-Torres, M. A. Participants responded more quickly on high- relative to low-probability-reinforced trials [RT adaptive salience: F(1, 35)=9.5, p=0.004, partial 2=0.213]. Reference McGowan, Lawrence, Sales, Quested and Grasby2004). Freeman, Tom P. This study also reported that patients exhibited reduced haemodynamic correlates of reward prediction errors in the ventral striatum relative to controls, consistent with other findings in medicated patients (Juckel et al. Aberrant salience calculated from subjective reinforcement probability ratings in patients with schizophrenia. Fernandez-Rivas, A. Reference Jensen, Willeit, Zipursky, Savina, Smith, Menon, Crawley and Kapur2008), consistent with aberrant salience hypothesis. H.E.M. Reference Garety, Hemsley and Wessely1991) was included. Our fourth prediction was that in the controls, individual differences in aberrant salience would be related to the personality trait of schizotypy, considered to be an index of psychosis proneness (Chapman et al. However, such explanations cannot explain differences in our measure of aberrant salience between symptom subgroups, or the correlation with schizotypy in the healthy volunteers. The final diagnoses were schizophrenia in 19 patients and schizoaffective disorder in the remaining patient. Aberrant salience was defined as the absolute difference in RT (implicit) or VAS rating (explicit) between the two levels of the task-irrelevant stimulus dimension (collapsing across the task-relevant stimulus dimension). Relationship between the sum of global scores from the Scale for the Assessment of Negative Symptoms (SANS) and aberrant salience (calculated from subjective reinforcement probability ratings). Participants rated high-probability-reinforced trials as more likely to yield reward than low-probability-reinforced trials [VAS adaptive salience: F(1, 35)=54.3, p<0.001, partial 2=0.608]. On reinforced trials where participants either made no response or responded after the probe had disappeared, the message Missed: 5 pence was displayed. Roiser, Jonathan P The aberrant salience hypothesis warrants further investigation in unmedicated patients with schizophrenia. Group (patient/control) was the between-subjects variable in both analyses. Knutson et al. However, the difference in VAS aberrant salience between patients with and without positive symptoms remained significant when negative symptoms were included as a covariate [F(1, 17)=5.5, p=0.032], and the difference in VAS aberrant salience between patients with and without negative symptoms remained significant when positive symptoms were included as a covariate [F(1, 17)=10.5, p=0.005]. Probability of reinforcement varied over one of these dimensions (task-relevant), but not the other (task-irrelevant). Emrich, Hinderk M. Nevertheless it will be important to confirm our findings in unmedicated patients. Rauch, Scott L. Surprisingly, patients with negative symptoms [n=12, mean sum of SANS global scores 8.9 (s.d.=5.1)] exhibited significantly greater VAS aberrant salience than those without (n=8) (t(18)=3.5, p=0.003, Cohen's d=1.6). If the trial was not reinforced, the message Sorryno money available was displayed. Das, Ravi K. Patients with positive symptoms did not differ from those with no positive symptoms on VAS adaptive salience [delusions: 16.7 (s.d.=28.4mm); no delusions: 17.3 (s.d.=29.4) mm, t(18)=0.05, p=0.96]. Huf, Gisele If dopamine transmission is dysregulated in psychosis (Abi-Dargham, Reference Abi-Dargham2004), it is possible that false negatives in the phasic dopamine signal might occur, i.e. Reference Young, Biggs, Ziegler and Meyer1978). Reward, motivation, and reinforcement learning, Reasoning in deluded schizophrenic and paranoid patients. Menon, Mahesh When participants responded more quickly than their mean RT, the message Quickvery good: X pence was displayed (for responses up to 1.5 SDFs faster than their mean RT) and Very quickexcellent: X pence (for responses faster than their mean RT by at least 1.5 SDFs). Bentall, R.

Gerretsen, Philip Arancio, Ottavio Chuhma, Nao Each CS comprised two visual dimensions, colour and form. Boucher, Aurelie A. Reference Laruelle, Abi-Dargham, van Dyck, Gil, DSouza, Erdos, McCance, Rosenblatt, Fingado, Zoghbi, Baldwin, Seibyl, Krystal, Charney and Innis1996; Abi-Dargham et al. 2. A World Health Organization ten-country study, Psychological Medicine (Monograph Supplement), The formation of abnormal associations in schizophrenia: neural and behavioral evidence, Cognitive heterogeneity in first-episode schizophrenia, Dysfunction of ventral striatal reward prediction in schizophrenia, Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia, Chaotic behavior in dopamine neurodynamics, Amphetamine modulates human incentive processing, Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects, Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study, Striatal dopamine in reward and attention: a system for understanding the symptomatology of acute schizophrenia and mania, The influence of expected value on saccadic preparation, Substantia nigra/ventral tegmental reward prediction error disruption in psychosis, Dopamine-dependent prediction errors underpin reward-seeking behaviour in humans, Synthesizing schizophrenia: a bottom-up, symptomatic approach, Deficit symptoms in schizophrenia: negative symptoms, Dopamine neurons and their role in reward mechanisms, A neural substrate of prediction and reward, Differential encoding of losses and gains in the human striatum, Delusions, superstitious conditioning and chaotic dopamine neurodynamics, The Mini-International Neuropsychiatric Interview (M.I.N.I. Holt, Daphne. Kapur, Shitij On these practice sessions, a fixation cross appeared at the beginning of each trial. was supported by a Wellcome Trust Ph.D. studentship. 2009. Reference Stefanis, Van Os, Avramopoulos, Smyrnis, Evdokimidis, Hantoumi and Stefanis2004). At the end of each block, participants indicated, using 10mm visual analogue scales (VAS), their estimate of the reinforcement probabilities for each of the four different CSs. It is possible that the differences in aberrant salience between the patients with and without delusions might also be explained by non-specific cognitive impairments in symptomatic patients, since such impairments might result in a failure to understand the task, difficulty in representing probabilities or a general tendency to respond more randomly.

Positive and negative symptoms were correlated in the patients (r=0.50, p=0.027). YMRS and CDRSS score were not correlated with either adaptive or aberrant salience. This grouping was performed on the basis of the sum of the global scores on the SAPS, either zero (no positive symptoms) or greater than zero (positive symptoms). Exclusion criteria were: known psychiatric or neurological disorder; medical disorder likely to lead to cognitive impairment; intelligence quotient (IQ) <70; recent illicit substance use and first-degree relatives diagnosed with a psychotic illness. For example, if colour was the reinforced dimensions, 14 out of 16 blue animals and 14 out of 16 blue household objects would be reinforced, compared with only two out of 16 red animals and two out of 16 red household objects. 1). Bartholomeusz, Cali * Patients exhibited reduced adaptive salience relative to controls (, Adaptive salience based on subjective reinforcement probability ratings in patients with schizophrenia and controls. The money won on each trial was added to the participant's running total for that block, Y, which was displayed underneath the feedback: TotalY. After 2.25s, auditory and visual feedback was presented for 1.5s (see Fig. This effect appeared to be driven by the presence of delusions and not hallucinations. Such models elegantly account for changes in both the firing patterns of ventral tegmental area dopamine neurons in monkeys (Schultz, Reference Schultz1997), and ventral striatal responses in humans (Pessiglione et al. Small, Scott A We tested a relatively small sample of patients with schizophrenia and performed multiple statistical comparisons, raising the likelihood of type I error. Following a variable interval (minimum 0.5s, maximum 1.5s) the probe appeared, and participants responded by pressing a button as quickly as possible. increasing the potential for a false positive). Reference Taylor, Phan, Britton and Liberzon2005) positive emotional stimuli relative to controls. Galdos, M. Reference Mason, Linney and Claridge2005). for this article. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? c We defined aberrant salience as quicker responding to or higher subjective reinforcement probability rating for one level of the task-irrelevant stimulus dimension relative to the other level (see b above). SAT and digit-span data were analysed using repeated-measures analysis of variance. The diagnosis was ascertained using a structured interview, the diagnostic module of the Diagnostic Interview for Psychosis (Jablensky et al. Hostname: page-component-8669ff84db-n6wqh In the same study, amphetamine administration caused significant phasic haemodynamic responses in the ventral striatum following CS+ that signalled potential monetary loss, an effect that was absent under placebo, possibly reflecting a loss of specificity of dopamine signalling (i.e. Reference Chapman, Chapman, Kwapil, Eckblad and Zinser1994; Claridge, Reference Claridge1994; Stefanis et al. Motivation and performance in schizophrenia. Remington, Gary J.P.R. (Reference Knutson, Bjork, Fong, Hommer, Mattay and Weinberger2004) found that amphetamine administration paradoxically decreased the magnitude of phasic ventral striatal haemodynamic responses in response to a CS+ that signalled reward (i.e. Fig. Anderson, Adam K. 2010. Reference Schultz, Dayan and Montague1997). 2009. 2011. and Dillo, Wolfgang On 50% of trials, participants won more money for quicker responses. and RT, Reaction time; VAS, visual analogue scale. Patients with delusions exhibited significantly greater aberrant salience than those without delusions, and aberrant salience also correlated with negative symptoms. increasing the potential for a false negative). Neubeck, Anna-Karin IQ, Intelligence quotient; WTAR, Wechsler Test of Adult Reading; O-LIFE, OxfordLiverpool Inventory of Feelings and Experiences; SAPS, Scale for the Assessment of Positive Symptoms; SANS, Scale for the Assessment of Negative Symptoms. Therefore persistent symptoms in medicated patients might still be related to aberrant salience. The Salience Attribution Test. DeLisi, Lynn E. Patients and controls were well matched for gender distribution, age and pre-morbid IQ (see Table 1). Rayport, Stephen Please accept our apologies for any inconvenience caused. Close this message to accept cookies or find out how to manage your cookie settings. The conditioned stimuli appearing before the response are coloured either red or blue. Controls exhibited significant RT adaptive salience [F(1, 16)=9.8, p=0.007, partial 2=0.379], but patients did not (F<1, partial 2=0.030) (see Fig. Three patients were unmedicated at the time of testing, two were taking first-generation drugs (haloperidol, flupenthixol), and 15 second-generation drugs (five olanzapine, four aripiprazole, two quetiapine, two risperidone, one clozapine and one a combination of aripiprazole and quetiapine). and In summary, these data are consistent with the hypothesis that schizophrenia patients with delusions exhibit aberrant salience. Online purchasing will be unavailable on Sunday 24th July between 8:00 and 13:30 BST due to essential maintenance work. O'Shea, Anne Furthermore, the only other study investigating stimulusreinforcement learning for appetitive outcomes in psychosis found that both medicated and unmedicated patients responded more quickly to a CS than controls, a finding interpreted as aberrant salience (Murray et al. "useRatesEcommerce": false, For RT, aberrant salience is computed as: irrelevant low RTirrelevant high RT. Positive symptoms showed a trend towards correlating with VAS aberrant salience (rho=0.40, p=0.085). Reference Jensen, Willeit, Zipursky, Savina, Smith, Menon, Crawley and Kapur2008), we also found impaired learning of stimulusreinforcement associations (indexed by a reduction in adaptive salience) in medicated patients with schizophrenia, which we hypothesize is related to dopamine D2 receptor blockade (Cutmore & Beninger, Reference Cutmore and Beninger1990). No monetary reinforcement was provided during the practice sessions. Since aberrant salience is defined as any deviation from equal reaction time or subjective reinforcement probability rating for the two levels of the task-irrelevant stimulus dimension, the sign is unimportant. McIntosh, Andrew M. Woodberry, Kristen A. Do patients with schizophrenia exhibit aberrant salience? Wang, X.-J. This study was funded by the Raymond Way Fund, University College London, and the Wellcome Trust (grant number 064607/Z/01/Z). If phasic dopamine release signals reinforcement prediction errors, any large stochastic fluctuation in dopamine release may disrupt learning about stimulusreinforcement associations, generating a state in which motivational salience could be misattributed to neutral stimuli, or what might be termed a false-positive phasic dopamine signal; such events have been proposed to result in positive symptoms (Kapur, Reference Kapur2003). Amer, G. Miller, Gretchen M Values are given as mean (standard deviation).

Romaniuk, Liana To investigate the hypothesis that aberrant salience was related to positive symptoms of schizophrenia, we divided the patients into those with and without positive symptoms when analysing SAT data. In the present study, patients for whom medication had effectively eliminated positive symptoms actually exhibited significantly less aberrant salience than controls, supporting the hypothesis that the beneficial effects of antipsychotic medications on positive symptoms are related to their ability to dampen-down aberrant salience (Kapur, Reference Kapur2003). It has been hypothesized that dopamine antagonists reduce both adaptive and aberrant salience, and that in the absence of effective treatment patients with schizophrenia exhibit aberrant salience (Kapur, Reference Kapur2003). Reference Murray, Corlett, Clark, Pessiglione, Blackwell, Honey, Jones, Bullmore, Robbins and Fletcher2008). In this longitudinal study, participants are contacted 1 and 3 years after presentation for repeat assessments, at which time the diagnosis is reviewed. Gaisler-Salomon, Inna The likelihood that money was available on a trial was signalled by one of four CS that appeared at the top and bottom of the screen before the onset of the probe. Galloway, Matthew P

Reference Joyce, Hutton, Mutsatsa and Barnes2005). In both cases, symptom group was entered as the between-subjects variable. CSs varied on two different visual dimensions: colour (blue or red) and shape (animal or household object). Freudenreich, Oliver and These data support the hypothesis that aberrant salience is related to the presence of delusions in medicated patients with schizophrenia, but are also suggestive of a link with negative symptoms. Negative symptoms also showed a trend towards correlating negatively with VAS adaptive salience (r=0.42, p=0.068), though patients with negative symptoms did not differ significantly from those without negative symptoms on VAS adaptive salience [no negative symptoms: 28.6 (s.d.=25.2) mm; negative symptoms: mean 9.5 (s.d.=28.5) mm, t(18)=1.5, p=0.14]. Patients exhibited reduced adaptive salience relative to controls, but the two groups did not differ in terms of aberrant salience. Pictures that appeared just before the onset of the probe signalled the probability that the participant would win money on a given trial, which occurred on 50% of trials. A number of theorists have hypothesized that positive psychotic symptoms may be related to abnormal learning of stimulusreinforcement associations (King et al. Morgan, Celia J. Schmitz, Taylor W. El Kissi, Yousri Our second prediction was that medicated patients with schizophrenia would exhibit equivalent aberrant salience to controls, representing the beneficial effect of anti-psychotic medication, which is hypothesized to normalize aberrant salience from a previously elevated level (Kapur, Reference Kapur2003). Lakshmanan, Balaji Riecansky, Igor 4. Reference Hietala, Syvalahti, Vuorio, Rakkolainen, Bergman, Haaparanta, Solin, Kuoppamaki, Kirvela and Ruotsalainen1995; Abi-Dargham, Reference Abi-Dargham2004; McGowan et al. Mamo, David Further, it is possible that the finding of reduced adaptive salience in the patients might simply reflect a learning deficit independent of reward, or perhaps a difficulty in using informative cues to guide speeded responses (Robbins, Reference Robbins2005), which could be related either to the illness or the effects of antipsychotic medication (Pessiglione et al. Has data issue: true and Studies in experimental animals have demonstrated that stimuli that are repeatedly associated with reward, termed conditioned stimuli (CS+), are able to elicit phasic dopamine firing in the midbrain when presented alone, while stimuli that do not predict reward (CS) do not elicit such a response (Schultz et al. Adaptive salience based on latency in patients with schizophrenia and controls. van Os, J. Therefore, our first prediction was that that medicated patients with schizophrenia would exhibit reduced adaptive salience relative to controls, representing an undesirable side-effect of anti-psychotic medication. hasContentIssue false. Hence, the SAT is relatively straightforward to perform for patients, since it simply requires participants to respond as quickly as they can when the probe appears on the screen. Reference Addington, Addington and Schissel1990) and the Young Mania Scale (YMRS; Young et al. Lanfermann, Heinrich J. Korostil, Michele and Again, consistent with our first prediction, controls exhibited greater VAS adaptive salience than patients [groupprobability interaction: F(1, 35)=10.9, p=0.002, partial 2=0.238], though VAS adaptive salience was significant in both groups [controls: F(1, 16)=71.9, p<0.001, partial 2=0.818; patients: F(1, 19)=7.3, p=0.014, partial 2=0.279] (see Fig. To test this hypothesis we investigated whether patients with schizophrenia showed impaired learning of task-relevant stimulusreinforcement associations in the presence of distracting task-irrelevant cues. Stefanovic, Ana and To assess whether aberrant salience might be related to the jumping to conclusions bias previously reported in schizophrenia (Garety et al. Reference Sheehan, Lecrubier, Sheehan, Amorim, Janavs, Weiller, Hergueta, Baker and Dunbar1998). Demographic data and data from the Beads Task were analysed using independent samples t tests and 2 tests. 2011. The reward was scaled according to X=10+90(mean RTtrial RT)/(3SDF), up to a maximum of 100 pence. Studies investigating Pavlovian conditioning in medicated patients found a deficit in learning stimulusreinforcement associations (Garmezy, Reference Garmezy1952; Cohen, Reference Cohen1956; Waltz et al. Published online by Cambridge University Press: Curran, H. Valerie Myin-Germeys, I. Healthy volunteers completed the short-form of the OxfordLiverpool Inventory of Feelings and Experiences schizotypy questionnaire (O-LIFE; Mason et al. Owolabi, Olasunmbo O. Presentation of a CS+ has also been shown to increase the speed of responding relative to the presentation of a CS, an effect that is modulated by ventral striatal dopamine (Wyvell & Berridge, Reference Wyvell and Berridge2000). Participants did not reliably rate any particular irrelevant stimulus feature as more likely to be associated with reward relative to the other (p>0.05 for all). For the main test, the mean, minimum and maximum probe durations were calculated from the second practice session in the same way. b We defined, for each subject, high and low irrelevant levels on the task-irrelevant stimulus dimension based on their responses: for RT, high denotes whichever level participants responded faster to; for VAS, high denotes whichever level participants rated as more likely to result in reinforcement. Two measures of motivational salience were calculated for each block. To assess whether any abnormalities on the SAT might be related to neurocognitive impairments in the patient group, pre-morbid IQ was estimated using the Wechsler Test of Adult Reading (WTAR; Wechsler, Reference Wechsler2001) and working memory with the forwards and backwards digit-span (Wechsler, Reference Wechsler1981). For VAS, aberrant salience is computed as: irrelevant high VAS ratingirrelevant low VAS rating. Most recently, Kapur (Reference Kapur2003) proposed that the positive symptoms of schizophrenia may arise out of the aberrant assignment of salience to external objects and internal representations, and that antipsychotic medications reduce positive symptoms, by attenuating aberrant motivational salience, via blockade of the dopamine D2 receptor. On 50% of trials, participants won more money for quicker responses. Consistent with this explanation, other studies that investigated responses to emotionally salient images in medicated patients with schizophrenia reported decreased responding for (Heerey & Gold, Reference Heerey and Gold2007) and ventral striatal responses to (Taylor et al. Reference Abi-Dargham, Rodenhiser, Printz, Zea-Ponce, Gil, Kegeles, Weiss, Cooper, Mann, Van Heertum, Gorman and Laruelle2000; Abi-Dargham, Reference Abi-Dargham2004; McGowan et al. For VAS, adaptive salience is computed as: high reinforcement probability VAS ratinglow reinforcement probability VAS rating. For all analyses a p value of <0.05 was considered significant while 0.05

of the fastest half of the trials (SDF) was also calculated, and was used to set the minimum and maximum probe durations for the second practice session (mean from first practice session2SDF).