Delusions, a core symptom of psychosis, are false beliefs that are rigidly held with strong conviction despite contradictory evidence. Alterations in inferential processes have long been proposed to underlie delusional pathology, but previous attempts to show this have failed to yield compelling evidence for a specific relationship between inferential abnormalities and delusional severity in schizophrenia. Using a novel, incentivized information-sampling task (a modified version of the beads task), alongside well-characterized decision-making tasks, we sought a mechanistic understanding of delusions in a sample of medicated and unmedicated patients with schizophrenia who exhibited a wide range of delusion severity. In this novel task, participants chose whether to draw beads from one of two hidden jars or to guess the identity of the hidden jar, in order to minimize financial loss from a monetary endowment, and concurrently reported their probability estimates for the hidden jar. We found that patients with higher delusion severity exhibited increased information seeking (i.e. increased draws-to-decision behaviour). This increase was highly specific to delusion severity as compared to the severity of other psychotic symptoms, working-memory capacity, and other clinical and socio-demographic characteristics. Delusion-related increases in information seeking were present in unmedicated patients, indicating that they were unlikely due to antipsychotic medication. In addition, after adjusting for delusion severity, patients as a whole exhibited decreased information seeking relative to healthy individuals, a decrease that correlated with lower socioeconomic status. Computational analyses of reported probability estimates further showed that more delusional patients exhibited abnormal belief updating characterized by stronger reliance on prior beliefs formed early in the inferential process, a feature that correlated with increased information seeking in patients. Other decision-making parameters that could have theoretically explained the delusion effects, such as those related to subjective valuation, were uncorrelated with both delusional severity and information seeking among the patients. In turn, we found some preliminary evidence that subjective valuation (rather than belief updating) may explain group differences in information seeking unrelated to delusions. Together, these results suggest that abnormalities in belief updating, characterized by stronger reliance on prior beliefs formed by incorporating information presented earlier in the inferential process, may be a core computational mechanism of delusional ideation in psychosis. Our results thus provide direct empirical support for an inferential mechanism that naturally captures the characteristic rigidity associated with delusional beliefs.

Context Chronic cocaine use has been associated with structural deficits in brain regions having dopamine receptive neurons. However, the concomitant use of other drugs and common genetic variability in monoamine regulation present additional structural variability. Objective To examine variations in gray matter volume (GMV) as a function of lifetime drug use and the monoamine oxidase A (MAOA) genotype in men with cocaine use disorders (CUD) and healthy male controls. Design Cross-sectional comparison between 40 CUD and 42 controls scanned with magnetic resonance imaging (MRI) to assess GMV and genotyped for the MAOA polymorphism. The impact of cocaine addiction on GM was tested by 1) comparing CUD with controls, 2) testing diagnosis-by-MAOA interactions, and 3) correlating GMV with lifetime cocaine, alcohol, and cigarette smoking, and testing their unique contribution to GM beyond other factors. Outcome Measures GMV were derived from MRI with voxel-based-morphometry. Genotyping was performed for a functional polymorphism (a variable number tandem repeat or VNTR) in the promoter region of the MAOA gene with “high” and “low” alleles. Results 1) Individuals with CUD had reductions in GMV in the orbitofrontal (OFC), dorsolateral prefrontal (DLPFC) and temporal cortex, and hippocampus, compared to controls. 2) The OFC reductions were uniquely driven by CUD with low MAOA genotype and by lifetime cocaine use. 3) GMV in the DLPFC and hippocampus, was driven by lifetime alcohol use beyond the genotype and other pertinent variables. Conclusions This study documents for the first time, the enhanced sensitivity of CUD low MAOA carriers to GM loss, specifically in the OFC, indicating that this genotype may exacerbate the deleterious effects of cocaine in the brain. In addition, chronic alcohol use was a major contributor to GM loss in the DLPFC and hippocampus, and is likely to further impair executive function and learning in cocaine addiction.

Learning can be guided by unexpected success or failure, signaled via dopaminergic positive reward prediction error (ϩRPE) and negative reward-prediction error (ϪRPE) signals, respectively. Despite conflicting empirical evidence, RPE signaling is thought to be impaired in drug addiction. To resolve this outstanding question, we studied as a measure of RPE the feedback negativity (FN) that is sensitive to both reward and the violation of expectation. We examined FN in 25 healthy controls; 25 individuals with cocaine-use disorder (CUD) who tested positive for cocaine on the study day (CUDϩ), indicating cocaine use within the past 72 h; and in 25 individuals with CUD who tested negative for cocaine (CUDϪ). EEG was acquired while the participants performed a gambling task predicting whether they would win or lose money on each trial given three known win probabilities (25, 50, or 75%). FN was scored for the period in each trial when the actual outcome (win or loss) was revealed. A significant interaction between prediction, outcome, and group revealed that controls showed increased FN to unpredicted compared with predicted wins (i.e., intact ϩRPE) and decreased FN to unpredicted compared with predicted losses (i.e., intact ϪRPE). However, neither CUD subgroup showed FN modulation to loss (i.e., impaired ϪRPE), and unlike CUDϩ individuals, CUDϪ individuals also did not show FN modulation to win (i.e., impaired ϩRPE). Thus, using FN, the current study directly documents ϪRPE deficits in CUD individuals. The mechanisms underlying ϪRPE signaling impairments in addiction may contribute to the disadvantageous nature of excessive drug use, which can persist despite repeated unfavorable life experiences (e.g., frequent incarcerations).

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