The impact of spectral basis set composition on estimated levels of cingulate glutamate and its associations with different personality traits.

BACKGROUND: 1H-MRS is increasingly used in basic and clinical research to explain brain function and alterations respectively. In psychosis research it is now one of the main tools to investigate imbalances in the glutamatergic system. Interestingly, however, the findings are extremely variable even within patients of similar disease states. One reason may be the variability in analysis strategies, despite suggestions for standardization. Therefore, our study aimed to investigate the extent to which the basis set configuration- which metabolites are included in the basis set used for analysis- would affect the spectral fit and estimated glutamate (Glu) concentrations in the anterior cingulate cortex (ACC), and whether any changes in levels of glutamate would be associated with psychotic-like experiences and autistic traits. METHODS: To ensure comparability, we utilized five different exemplar basis sets, used in research, and two different analysis tools, r-based spant applying the ABfit method and Osprey using the LCModel. RESULTS: Our findings revealed that the types of metabolites included in the basis set significantly affected the glutamate concentration. We observed that three basis sets led to more consistent results across different concentration types (i.e., absolute Glu in mol/kg, Glx (glutamate + glutamine), Glu/tCr), spectral fit and quality measurements. Interestingly, all three basis sets included phosphocreatine. Importantly, our findings also revealed that glutamate levels were differently associated with both schizotypal and autistic traits depending on basis set configuration and analysis tool, with the same three basis sets showing more consistent results. CONCLUSIONS: Our study highlights that scientific results may be significantly altered depending on the choices of metabolites included in the basis set, and with that emphasizes the importance of carefully selecting the configuration of the basis set to ensure accurate and consistent results, when using MR spectroscopy. Overall, our study points out the need for standardized analysis pipelines and reporting.

Association between increased anterior cingulate glutamate and psychotic-like experiences, but not autistic traits in healthy volunteers.

Despite many differences, autism spectrum disorder and schizophrenia spectrum disorder share environmental risk factors, genetic predispositions as well as neuronal abnormalities, and show similar cognitive deficits in working memory, perspective taking, or response inhibition. These shared abnormalities are already present in subclinical traits of these disorders. The literature proposes that changes in the inhibitory GABAergic and the excitatory glutamatergic system could explain underlying neuronal commonalities and differences. Using magnetic resonance spectroscopy (1H-MRS), we investigated the associations between glutamate concentrations in the anterior cingulate cortex (ACC), the left/right putamen, and left/right dorsolateral prefrontal cortex and psychotic-like experiences (Schizotypal Personality Questionnaire) and autistic traits (Autism Spectrum Quotient) in 53 healthy individuals (26 women). To investigate the contributions of glutamate concentrations in different cortical regions to symptom expression and their interactions, we used linear regression analyses. We found that only glutamate concentration in the ACC predicted psychotic-like experiences, but not autistic traits. Supporting this finding, a binomial logistic regression predicting median-split high and low risk groups for psychotic-like experiences revealed ACC glutamate levels as a significant predictor for group membership. Taken together, this study provides evidence that glutamate levels in the ACC are specifically linked to the expression of psychotic-like experiences, and may be a potential candidate in identifying early risk individuals prone to developing psychotic-like experiences.

Fighting Post-COVID and ME/CFS - development of curative therapies.

The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation have been identified as potential mechanisms. However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). No curative therapies are available for ME/CFS or PCS. The mechanisms identified so far provide targets for therapeutic interventions. To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping.

A multicentre study on grey matter morphometric biomarkers for classifying early schizophrenia and parkinson's disease psychosis.

Psychotic symptoms occur in a majority of schizophrenia patients and in ~50% of all Parkinson's disease (PD) patients. Altered grey matter (GM) structure within several brain areas and networks may contribute to their pathogenesis. Little is known, however, about transdiagnostic similarities when psychotic symptoms occur in different disorders, such as in schizophrenia and PD. The present study investigated a large, multicenter sample containing 722 participants: 146 patients with first episode psychosis, FEP; 106 individuals in at-risk mental state for developing psychosis, ARMS; 145 healthy controls matching FEP and ARMS, Con-Psy; 92 PD patients with psychotic symptoms, PDP; 145 PD patients without psychotic symptoms, PDN; 88 healthy controls matching PDN and PDP, Con-PD. We applied source-based morphometry in association with receiver operating curves (ROC) analyses to identify common GM structural covariance networks (SCN) and investigated their accuracy in identifying the different patient groups. We assessed group-specific homogeneity and variability across the different networks and potential associations with clinical symptoms. SCN-extracted GM values differed significantly between FEP and Con-Psy, PDP and Con-PD, PDN and Con-PD, as well as PDN and PDP, indicating significant overall grey matter reductions in PD and early schizophrenia. ROC analyses showed that SCN-based classification algorithms allow good classification (AUC ~0.80) of FEP and Con-Psy, and fair performance (AUC ~0.72) when differentiating PDP from Con-PD. Importantly, the best performance was found in partly the same networks, including the thalamus. Alterations within selected SCNs may be related to the presence of psychotic symptoms in both early schizophrenia and PD psychosis, indicating some commonality of underlying mechanisms. Furthermore, results provide evidence that GM volume within specific SCNs may serve as a biomarker for identifying FEP and PDP.

Action selection in early stages of psychosis: an active inference approach.

BACKGROUND: To interact successfully with their environment, humans need to build a model to make sense of noisy and ambiguous inputs. An inaccurate model, as suggested to be the case for people with psychosis, disturbs optimal action selection. Recent computational models, such as active inference, have emphasized the importance of action selection, treating it as a key part of the inferential process. Based on an active inference framework, we sought to evaluate previous knowledge and belief precision in an action-based task, given that alterations in these parameters have been linked to the development of psychotic symptoms. We further sought to determine whether task performance and modelling parameters would be suitable for classification of patients and controls. METHODS: Twenty-three individuals with an at-risk mental state, 26 patients with first-episode psychosis and 31 controls completed a probabilistic task in which action choice (go/no-go) was dissociated from outcome valence (gain or loss). We evaluated group differences in performance and active inference model parameters and performed receiver operating characteristic (ROC) analyses to assess group classification. RESULTS: We found reduced overall performance in patients with psychosis. Active inference modelling revealed that patients showed increased forgetting, reduced confidence in policy selection and less optimal general choice behaviour, with poorer action-state associations. Importantly, ROC analysis showed fair-to-good classification performance for all groups, when combining modelling parameters and performance measures. LIMITATIONS: The sample size is moderate. CONCLUSION: Active inference modelling of this task provides further explanation for dysfunctional mechanisms underlying decision-making in psychosis and may be relevant for future research on the development of biomarkers for early identification of psychosis.

Neural Circuitry of Salience and Reward Processing in Psychosis.

The 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. We argue that the origin of salience and reward processing dysfunctions may be centered in the subcortex during the earliest stages of psychosis, with cortical abnormalities being initially more spared but becoming more prominent in established psychotic illness/schizophrenia. The neural circuits underpinning salience and reward processing may provide targets for delaying or preventing progressive behavioral and neurobiological decline.

Negative symptoms, striatal dopamine and model-free reward decision-making in schizophrenia.

Negative symptoms, such as lack of motivation or social withdrawal, are highly prevalent and debilitating in patients with schizophrenia. Underlying mechanisms of negative symptoms are incompletely understood, thereby preventing the development of targeted treatments. We hypothesized that in patients with schizophrenia during psychotic remission, impaired influences of both model-based and model-free reward predictions on decision-making ('reward prediction influence', RPI) underlie negative symptoms. We focused on psychotic remission, because psychotic symptoms might confound reward-based decision-making. Moreover, we hypothesized that impaired model-based/model-free RPIs depend on alterations of both associative striatum dopamine synthesis and storage (DSS) and executive functioning. Both factors influence RPI in healthy subjects and are typically impaired in schizophrenia. Twenty-five patients with schizophrenia with pronounced negative symptoms during psychotic remission and 24 healthy controls were included in the study. Negative symptom severity was measured by the Positive and Negative Syndrome Scale negative subscale, model-based/model-free RPI by the two-stage decision task, associative striatum DSS by 18F-DOPA positron emission tomography and executive functioning by the symbol coding task. Model-free RPI was selectively reduced in patients and associated with negative symptom severity as well as with reduced associative striatum DSS (in patients only) and executive functions (both in patients and controls). In contrast, model-based RPI was not altered in patients. Results provide evidence for impaired model-free reward prediction influence as a mechanism for negative symptoms in schizophrenia as well as for reduced associative striatum dopamine and executive dysfunction as relevant factors. Data suggest potential treatment targets for patients with schizophrenia and pronounced negative symptoms.

Investigating the relationship of COVID-19 related stress and media consumption with schizotypy, depression, and anxiety in cross-sectional surveys repeated throughout the pandemic in Germany and the UK.

Background: Studies report a strong impact of the COVID-19 pandemic and related stressors on the mental well-being of the general population. In this paper, we investigated whether COVID-19 related concerns and social adversity affected schizotypal traits, anxiety, and depression using structural equational modelling. In mediation analyses, we furthermore explored whether these associations were mediated by healthy (sleep and physical exercise) or unhealthy behaviours (drug and alcohol consumption, excessive media use). Methods: We assessed schizotypy, depression, and anxiety as well as healthy and unhealthy behaviours and a wide range of sociodemographic scores using online surveys from residents of Germany and the United Kingdom over 1 year during the COVID-19 pandemic. Four independent samples were collected (April/May 2020: N=781, September/October 2020: N=498, January/February 2021: N=544, May 2021: N=486). The degree of schizotypy was measured using the Schizotypal Personality Questionnaire (SPQ), anxiety, and depression symptoms were surveyed with the Symptom Checklist (SCL-27), and healthy and unhealthy behaviours were assessed with the Coronavirus Health Impact Survey (CRISIS). Structural equation models were used to consider the influence of COVID-19 related concerns and social adversity on depressive and anxiety-related symptoms and schizotypal traits in relation to certain healthy (sleep and exercise) and unhealthy behaviours (alcohol and drug consumption, excessive media use). Results: The results revealed that COVID-19 related life concerns were significantly associated with schizotypy in the September/October 2020 and May 2021 surveys, with anxiety in the September/October 2020, January/February 2021, and May 2021 surveys, and with depressive symptoms in all surveys. Social adversity significantly affected the expression of schizotypal traits and depressive and anxiety symptoms in all four surveys. Importantly, we found that excessive media consumption (>4 hr per day) fully mediated the relationship between COVID-19 related life concerns and schizotypal traits in the January/February 2021 survey. Furthermore, several of the surveys showed that excessive media consumption was associated with increased depressive and anxiety-related symptoms in people burdened by COVID-19 related life. Conclusions: The ongoing uncertainties of the pandemic and the restrictions on social life have a strong impact on mental well-being and especially the expression of schizotypal traits. The negative impact is further boosted by excessive media consumption, which is especially critical for people with high schizotypal traits. Funding: FK received funding from the European Union's Horizon 2020 (Grant number 754,462). SN received funding from the Cundill Centre for Child and Youth Depression at the Centre for Addiction and Mental Health, Toronto, Canada and the Wellcome Trust Institutional Strategic Support Fund from the University of Cambridge.

The 2020 COVID-19 pandemic, and the measures different governments took to contain it, harmed many people's mental well-being. The restrictions, combined with pandemic-related uncertainty, caused many individuals to experience increased stress, depression, and anxiety. Many people turned to unhealthy behaviours to cope, including consuming more alcohol or drugs, using media excessively, developing poor sleeping habits, or reducing the amount of exercise they did. Stress, drugs, poor sleep, and uncertainty can increase an individual's risk of developing psychotic symptoms, including delusions, hallucinations, or difficulty thinking clearly. These symptoms may be temporary or part of a more lasting condition, like schizophrenia. The risk of developing these symptoms increases in people with 'schizotypal traits', such as a lack of close relationships, paranoia, or unusual or implausible beliefs. These individuals may be especially vulnerable to the harmful mental health effects of the pandemic. Daimer et al. demonstrated that people who were more worried about their life stability or financial situation during the 2020 COVID-19 pandemic had worse mental well-being than those who felt secure. In the experiments, volunteers completed a series of online mental health questionnaires at four different time points during the pandemic. People who reported feeling lonely, having negative thoughts, or experiencing fewer positive social interactions had more symptoms of mental illness. People who experienced more life disruptions also reported more anxiety or depression symptoms and more schizotypal traits. Daily consumption of at least four hours of digital media exacerbated negative mental health symptoms, and people with more pandemic-related life concerns also spent more time on digital media Daimer et al. suggest that increased media consumption among people with pandemic-related hardships may have increased mental health symptoms and schizotypal traits in these individuals. The survey results suggest that maintaining a healthy lifestyle, including meaningful relationships, is essential to staying mentally healthy during extreme situations like a global pandemic. Protective interventions ­ such as strengthening social support networks, providing mental health education, or increasing mental healthcare provisions ­ are essential to prevent poor mental health outcomes during future crises.

Survey of German medical students during the COVID-19 pandemic: attitudes toward volunteering versus compulsory service and associated factors.

Due to the spread of COVID-19, a key challenge was to reduce potential staff shortages in the healthcare sector. Besides recruiting retired healthcare workers, medical students were considered to support this task. Commitment of medical students in Germany during the COVID-19 pandemic was evaluated using an online survey, with particular focus on their burdens and anxieties. This survey was distributed to students within a 2-week period in April and May 2020. Ultimately, 1241 participants were included in the analysis. During the pandemic, 67.9% (65.3% to 70.5%) of the participants reported that they had volunteered. Furthermore, 88.9% (86.9% to 90.5%) stated that they were against compulsory recruitment in this context. Students who volunteered (committed students) had a significantly lower anxiety index than non-committed students. Additionally, students were more concerned about infecting other patients and relatives than themselves. Higher levels of anxiety were related to lower levels of commitment. A mandatory assignment during the pandemic was rejected by the students and does not seem to be necessary due to the large number of volunteers.

Subjective Impact of the COVID-19 Pandemic on Schizotypy and General Mental Health in Germany and the United Kingdom, for Independent Samples in May and in October 2020.

Studies reported a strong impact on mental health during the first wave of the COVID-19 pandemic in March-June, 2020. In this study, we assessed the impact of the pandemic on mental health in general and on schizotypal traits in two independent general population samples of the United Kingdom (May sample N: 239, October sample N: 126; participation at both timepoints: 21) and in two independent general population samples of Germany (May sample N: 543, October sample N: 401; participation at both timepoints: 100) using online surveys. Whereas general psychological symptoms (global symptom index, GSI) and percentage of responders above clinical cut-off for further psychological investigation were higher in the May sample compared to the October sample, schizotypy scores (Schizotypal Personality Questionnaire) were higher in the October sample. We investigated potential associations, using general linear regression models (GLM). For schizotypy scores, we found that loneliness, use of drugs, and financial burden were more strongly corrected with schizotypy in the October compared to the May sample. We identified similar associations for GSI, as for schizotypy scores, in the May and October samples. We furthermore found that living in the United Kingdom was related to higher schizotypal scores or GSI. However, individual estimates of the GLM are highly comparable between the two countries. In conclusion, this study shows that while the general psychological impact is lower in the October than the May sample, potentially showing a normative response to an exceptional situation; schizotypy scores are higher at the second timepoint, which may be due to a stronger impact of estimates of loneliness, drug use, and financial burden. The ongoing, exceptional circumstances within this pandemic might increase the risk for developing psychosis in some individuals. The development of general psychological symptoms and schizotypy scores over time requires further attention and investigation.

The impact of the COVID-19 pandemic on mental health in the general population: a comparison between Germany and the UK.

BACKGROUND: The COVID-19 pandemic has led to dramatic social and economic changes in daily life. First studies report an impact on mental health of the general population showing increased levels of anxiety, stress and depression. In this study, we compared the impact of the pandemic on two culturally and economically similar European countries: the UK and Germany. METHODS: Participants (UK = 241, German = 541) completed an online-survey assessing COVID-19 exposure, impact on financial situation and work, substance and media consumption, mental health using the Symptom-Check-List-27 (SCL-27) and the Schizotypal Personality Questionnaire. RESULTS: We found distinct differences between the two countries. UK responders reported a stronger direct impact on health, financial situation and families. UK responders had higher clinical scores on the SCL-27, and higher prevalence. Interestingly, German responders were less hopeful for an end of the pandemic and more concerned about their life-stability. CONCLUSION: As 25% of both German and UK responders reported a subjective worsening of the general psychological symptoms and 20-50% of German and UK responders reached the clinical cut-off for depressive and dysthymic symptoms as well as anxieties, it specifically shows the need for tailored intervention systems to support large proportions of the general public.

Aberrant striatal dopamine links topographically with cortico-thalamic dysconnectivity in schizophrenia.

Aberrant dopamine function in the dorsal striatum and aberrant intrinsic functional connectivity (iFC) between distinct cortical networks and thalamic nuclei are among the most consistent large-scale brain imaging findings in schizophrenia. A pathophysiological link between these two alterations is suggested by theoretical models based on striatal dopamine's topographic modulation of cortico-thalamic connectivity within cortico-basal-ganglia-thalamic circuits. We hypothesized that aberrant striatal dopamine links topographically with aberrant cortico-thalamic iFC, i.e. aberrant associative striatum dopamine is associated with aberrant iFC between the salience network and thalamus, and aberrant sensorimotor striatum dopamine with aberrant iFC between the auditory-sensorimotor network and thalamus. Nineteen patients with schizophrenia during remission of psychotic symptoms and 19 age- and sex-comparable control subjects underwent simultaneous fluorodihydroxyphenyl-l-alanine PET (18F-DOPA-PET) and resting state functional MRI (rs-fMRI). The influx constant kicer based on 18F-DOPA-PET was used to measure striatal dopamine synthesis capacity; correlation coefficients between rs-fMRI time series of cortical networks and thalamic regions of interest were used to measure iFC. In the salience network-centred system, patients had reduced associative striatum dopamine synthesis capacity, which correlated positively with decreased salience network-mediodorsal-thalamus iFC. This correlation was present in both patients and healthy controls. In the auditory-sensorimotor network-centred system, patients had reduced sensorimotor striatum dopamine synthesis capacity, which correlated positively with increased auditory-sensorimotor network-ventrolateral-thalamus iFC. This correlation was present in patients only. Results demonstrate that reduced striatal dopamine synthesis capacity links topographically with cortico-thalamic intrinsic dysconnectivity in schizophrenia. Data suggest that aberrant striatal dopamine and cortico-thalamic dysconnectivity are pathophysiologically related within dopamine-modulated cortico-basal ganglia-thalamic circuits in schizophrenia.

Influence of prior beliefs on perception in early psychosis: Effects of illness stage and hierarchical level of belief.

Alterations in the balance between prior expectations and sensory evidence may account for faulty perceptions and inferences leading to psychosis. However, uncertainties remain about the nature of altered prior expectations and the degree to which they vary with the emergence of psychosis. We explored how expectations arising at two different levels-cognitive and perceptual-influenced processing of sensory information and whether relative influences of higher- and lower-level priors differed across people with prodromal symptoms and those with psychotic illness. In two complementary auditory perception experiments, 91 participants (30 with first-episode psychosis, 29 at clinical risk for psychosis, and 32 controls) were required to decipher a phoneme within ambiguous auditory input. Expectations were generated in two ways: an accompanying visual input of lip movements observed during auditory presentation or through written presentation of a phoneme provided prior to auditory presentation. We determined how these different types of information shaped auditory perceptual experience, how this was altered across the prodromal and established phases of psychosis, and how this relates to cingulate glutamate levels assessed by magnetic resonance spectroscopy. The psychosis group relied more on high-level cognitive priors compared to both healthy controls and those at clinical risk for psychosis and relied more on low-level perceptual priors than the clinical risk group. The risk group was marginally less reliant on low-level perceptual priors than controls. The results are consistent with previous theory that influences of prior expectations in perceptions in psychosis differ according to level of prior and illness phase. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Reinforcement learning as an intermediate phenotype in psychosis? Deficits sensitive to illness stage but not associated with polygenic risk of schizophrenia in the general population.

BACKGROUND: Schizophrenia is a complex disorder in which the causal relations between risk genes and observed clinical symptoms are not well understood and the explanatory gap is too wide to be clarified without considering an intermediary level. Thus, we aimed to test the hypothesis of a pathway from molecular polygenic influence to clinical presentation occurring via deficits in reinforcement learning. METHODS: We administered a reinforcement learning task (Go/NoGo) that measures reinforcement learning and the effect of Pavlovian bias on decision making. We modelled the behavioural data with a hierarchical Bayesian approach (hBayesDM) to decompose task performance into its underlying learning mechanisms. Study 1 included controls (n = 29, F|M = 0.81), At Risk Mental State for psychosis (ARMS, n = 23, F|M = 0.35) and FEP (First-episode psychosis, n = 26, F|M = 0.18). Study 2 included healthy adolescents (n = 735, F|M = 1.06), 390 of whom had their polygenic risk scores for schizophrenia (PRSs) calculated. RESULTS: Patients with FEP showed significant impairments in overriding Pavlovian conflict, a lower learning rate and a lower sensitivity to both reward and punishment. Less widespread deficits were observed in ARMS. PRSs did not significantly predict performance on the task in the general population, which only partially correlated with measures of psychopathology. CONCLUSIONS: Reinforcement learning deficits are observed in first episode psychosis and, to some extent, in those at clinical risk for psychosis, and were not predicted by molecular genetic risk for schizophrenia in healthy individuals. The study does not support the role of reinforcement learning as an intermediate phenotype in psychosis.

Auditory Predictions and Prediction Errors in Response to Self-Initiated Vowels.

It has been suggested that speech production is accomplished by an internal forward model, reducing processing activity directed to self-produced speech in the auditory cortex. The current study uses an established N1-suppression paradigm comparing self- and externally initiated natural speech sounds to answer two questions: (1) Are forward predictions generated to process complex speech sounds, such as vowels, initiated via a button press? (2) Are prediction errors regarding self-initiated deviant vowels reflected in the corresponding ERP components? Results confirm an N1-suppression in response to self-initiated speech sounds. Furthermore, our results suggest that predictions leading to the N1-suppression effect are specific, as self-initiated deviant vowels do not elicit an N1-suppression effect. Rather, self-initiated deviant vowels elicit an enhanced N2b and P3a compared to externally generated deviants, externally generated standard, or self-initiated standards, again confirming prediction specificity. Results show that prediction errors are salient in self-initiated auditory speech sounds, which may lead to more efficient error correction in speech production.

Dopaminergic drug treatment remediates exaggerated cingulate prediction error responses in obsessive-compulsive disorder.

RATIONALE: Patients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function. OBJECTIVE: In this study, we investigate potential dopaminergic dysfunction during reward processing in the context of OCD. METHODS: We studied OCD patients (n = 18) and controls (n = 18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of a dopamine receptor agonist, pramipexole 0.5 mg; a dopamine receptor antagonist, amisulpride 400 mg; and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest. RESULTS: There were no significant group, drug, or interaction effects in the number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p = 0.089, partial ƞ2 = 0.1). In the imaging results, there was a significant interaction of group by drug (p = 0.013, partial ƞ2 = 0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p = 0.014, partial ƞ2 = 0.26, 1-ß error probability = 0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD. CONCLUSIONS: Our data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.

Cost Evaluation During Decision-Making in Patients at Early Stages of Psychosis.

Jumping to conclusions during probabilistic reasoning is a cognitive bias reliably observed in psychosis and linked to delusion formation. Although the reasons for this cognitive bias are unknown, one suggestion is that psychosis patients may view sampling information as more costly. However, previous computational modeling has provided evidence that patients with chronic schizophrenia jump to conclusions because of noisy decision-making. We developed a novel version of the classical beads task, systematically manipulating the cost of information gathering in four blocks. For 31 individuals with early symptoms of psychosis and 31 healthy volunteers, we examined the numbers of "draws to decision" when information sampling had no, a fixed, or an escalating cost. Computational modeling involved estimating a cost of information sampling parameter and a cognitive noise parameter. Overall, patients sampled less information than controls. However, group differences in numbers of draws became less prominent at higher cost trials, where less information was sampled. The attenuation of group difference was not due to floor effects, as in the most costly block, participants sampled more information than an ideal Bayesian agent. Computational modeling showed that, in the condition with no objective cost to information sampling, patients attributed higher costs to information sampling than controls did, Mann-Whitney U = 289, p = 0.007, with marginal evidence of differences in noise parameter estimates, t(60) = 1.86, p = 0.07. In patients, individual differences in severity of psychotic symptoms were statistically significantly associated with higher cost of information sampling, ρ = 0.6, p = 0.001, but not with more cognitive noise, ρ = 0.27, p = 0.14; in controls, cognitive noise predicted aspects of schizotypy (preoccupation and distress associated with delusion-like ideation on the Peters Delusion Inventory). Using a psychological manipulation and computational modeling, we provide evidence that early-psychosis patients jump to conclusions because of attributing higher costs to sampling information, not because of being primarily noisy decision makers.

Brain responses to different types of salience in antipsychotic naïve first episode psychosis: An fMRI study.

Abnormal salience processing has been suggested to contribute to the formation of positive psychotic symptoms in schizophrenia and related conditions. Previous research utilising reward learning or anticipation paradigms has demonstrated cortical and subcortical abnormalities in people with psychosis, specifically in the prefrontal cortex, the dopaminergic midbrain and the striatum. In these paradigms, reward prediction errors attribute motivational salience to stimuli. However, little is known about possible abnormalities across different forms of salience processing in psychosis patients, and whether any such abnormalities involve the dopaminergic midbrain. The aim of our study was, therefore, to investigate possible alterations in psychosis in neural activity in response to various forms of salience: novelty, negative emotion, targetness (task-driven salience) and rareness/deviance. We studied 14 antipsychotic naïve participants with first episode psychosis, and 37 healthy volunteers. During fMRI scanning, participants performed a visual oddball task containing these four forms of salience. Psychosis patients showed abnormally reduced signalling in the substantia nigra/ventral tegmental area (SN/VTA) for novelty, negative emotional salience and targetness; reduced striatal and occipital (lingual gyrus) signalling to novelty and negative emotional salience, reduced signalling in the amygdala, anterior cingulate cortex and parahippocamal gyrus to negative emotional salience, and reduced cerebellar signalling to novelty and negative emotional salience. Our results indicate alterations of several forms of salience processing in patients with psychosis in the midbrain SN/VTA, with additional subcortical and cortical regions also showing alterations in salience signalling, the exact pattern of alterations depending on the form of salience in question.

Abnormal reward prediction-error signalling in antipsychotic naive individuals with first-episode psychosis or clinical risk for psychosis.

Ongoing research suggests preliminary, though not entirely consistent, evidence of neural abnormalities in signalling prediction errors in schizophrenia. Supporting theories suggest mechanistic links between the disruption of these processes and the generation of psychotic symptoms. However, it is unknown at what stage in the pathogenesis of psychosis these impairments in prediction-error signalling develop. One major confound in prior studies is the use of medicated patients with strongly varying disease durations. Our study aims to investigate the involvement of the meso-cortico-striatal circuitry during reward prediction-error signalling in earliest stages of psychosis. We studied patients with first-episode psychosis (FEP) and help-seeking individuals at-risk for psychosis due to sub-threshold prodromal psychotic symptoms. Patients with either FEP (n = 14), or at-risk for developing psychosis (n = 30), and healthy volunteers (n = 39) performed a reinforcement learning task during fMRI scanning. ANOVA revealed significant (p < 0.05 family-wise error corrected) prediction-error signalling differences between groups in the dopaminergic midbrain and right middle frontal gyrus (dorsolateral prefrontal cortex, DLPFC). FEP patients showed disrupted reward prediction-error signalling compared to controls in both regions. At-risk patients showed intermediate activation in the midbrain that significantly differed from controls and from FEP patients, but DLPFC activation that did not differ from controls. Our study confirms that FEP patients have abnormal meso-cortical signalling of reward-prediction errors, whereas reward-prediction-error dysfunction in the at-risk patients appears to show a more nuanced pattern of activation with a degree of midbrain impairment but preserved cortical function.