Do the negative symptoms of schizophrenia reflect reduced responsiveness to reward? Examination using a reward prediction error (RPE) task.

BACKGROUND: A leading theory of the negative symptoms of schizophrenia is that they reflect reduced responsiveness to rewarding stimuli. This proposal has been linked to abnormal (reduced) dopamine function in the disorder, because phasic release of dopamine is known to code for reward prediction error (RPE). Nevertheless, few functional imaging studies have examined if patients with negative symptoms show reduced RPE-associated activations. METHODS: Matched groups of DSM-5 schizophrenia patients with high negative symptom scores (HNS, N = 27) or absent negative symptoms (ANS, N = 27) and healthy controls (HC, N = 30) underwent fMRI scanning while they performed a probabilistic monetary reward task designed to generate a measure of RPE. RESULTS: In the HC, whole-brain analysis revealed that RPE was positively associated with activation in the ventral striatum, the putamen, and areas of the lateral prefrontal cortex and orbitofrontal cortex, among other regions. Group comparison revealed no activation differences between the healthy controls and the ANS patients. However, compared to the ANS patients, the HNS patients showed regions of significantly reduced activation in the left ventrolateral and dorsolateral prefrontal cortex, and in the right lingual and fusiform gyrus. HNS and ANS patients showed no activation differences in ventral striatal or midbrain regions-of-interest (ROIs), but the HNS patients showed reduced activation in a left orbitofrontal cortex ROI. CONCLUSIONS: The findings do not suggest that a generalized reduction of RPE signalling underlies negative symptoms. Instead, they point to a more circumscribed dysfunction in the lateral frontal and possibly the orbitofrontal cortex.

Neural correlates of referential/persecutory delusions in schizophrenia: examination using fMRI and a virtual reality underground travel paradigm.

BACKGROUND: The brain functional correlates of delusions have been relatively little studied. However, a virtual reality paradigm simulating travel on the London Underground has been found to evoke referential ideation in both healthy subjects and patients with schizophrenia, making brain activations in response to such experiences potentially identifiable. METHOD: Ninety patients with schizophrenia/schizoaffective disorder and 28 healthy controls underwent functional magnetic resonance imaging while they viewed virtual reality versions of full and empty Barcelona Metro carriages. RESULTS: Compared to the empty condition, viewing the full carriage was associated with activations in the visual cortex, the cuneus and precuneus/posterior cingulate cortex, the inferior parietal cortex, the angular gyrus and parts of the middle and superior temporal cortex including the temporoparietal junction bilaterally. There were no significant differences in activation between groups. Nor were there activations associated with referentiality or presence of delusions generally in the patient group. However, patients with persecutory delusions showed a cluster of reduced activation compared to those without delusions in a region in the right temporal/occipital cortex. CONCLUSIONS: Performance of the metro task is associated with a widespread pattern of activations, which does not distinguish schizophrenic patients and controls, or show an association with referentiality or delusions in general. However, the finding of a cluster of reduced activation close to the right temporoparietal junction in patients with persecutory delusions specifically is of potential interest, as this region is believed to play a role in social cognition.

Combining MRI and clinical data to detect high relapse risk after the first episode of psychosis.

Detecting patients at high relapse risk after the first episode of psychosis (HRR-FEP) could help the clinician adjust the preventive treatment. To develop a tool to detect patients at HRR using their baseline clinical and structural MRI, we followed 227 patients with FEP for 18-24 months and applied MRIPredict. We previously optimized the MRI-based machine-learning parameters (combining unmodulated and modulated gray and white matter and using voxel-based ensemble) in two independent datasets. Patients estimated to be at HRR-FEP showed a substantially increased risk of relapse (hazard ratio = 4.58, P < 0.05). Accuracy was poorer when we only used clinical or MRI data. We thus show the potential of combining clinical and MRI data to detect which individuals are more likely to relapse, who may benefit from increased frequency of visits, and which are unlikely, who may be currently receiving unnecessary prophylactic treatments. We also provide an updated version of the MRIPredict software.

Negative schizophrenic symptoms as prefrontal cortex dysfunction: Examination using a task measuring goal neglect.

BACKGROUND: The negative symptoms of schizophrenia have been proposed to reflect prefrontal cortex dysfunction. However, this proposal has not been consistently supported in functional imaging studies, which have also used executive tasks that may not capture key aspects of negative symptoms such as lack of volition. METHOD: Twenty-four DSM-5 schizophrenic patients with high negative symptoms (HNS), 25 with absent negative symptoms (ANS) and 30 healthy controls underwent fMRI during performance of the Computerized Multiple Elements Test (CMET), a task designed to measure poor organization of goal directed behaviour or 'goal neglect'. Negative symptoms were rated using the PANSS and the Clinical Assessment Interview for Negative Symptoms (CAINS). RESULTS: On whole brain analysis, the ANS patients showed no significant clusters of reduced activation compared to the healthy controls. In contrast, the HNS patients showed hypoactivation compared to the healthy controls in the left anterior frontal cortex, the right dorsolateral prefrontal cortex (DLPFC), the anterior insula bilaterally and the bilateral inferior parietal cortex. When compared to the ANS patients, the HNS patients showed reduced activation in the left anterior frontal cortex, the left DLPFC and the left inferior parietal cortex. After controlling for disorganization scores, differences remained in clusters in the left anterior frontal cortex and the bilateral inferior parietal cortex. CONCLUSIONS: This study provides evidence that reduced prefrontal activation, perhaps especially in the left anterior frontal cortex, is a brain functional correlate of negative symptoms in schizophrenia. The simultaneous finding of reduced inferior parietal cortex activation was unexpected, but could reflect this region's involvement in cognitive control, particularly the 'regulative' component of this.

Age- and gender-related differences in brain tissue microstructure revealed by multi-component T2 relaxometry.

In spite of extensive work, inconsistent findings and lack of specificity in most neuroimaging techniques used to examine age- and gender-related patterns in brain tissue microstructure indicate the need for additional research. Here, we performed the largest Multi-component T2 relaxometry cross-sectional study to date in healthy adults (N = 145, 18-60 years). Five quantitative microstructure parameters derived from various segments of the estimated T2 spectra were evaluated, allowing a more specific interpretation of results in terms of tissue microstructure. We found similar age-related myelin water fraction (MWF) patterns in men and women but we also observed differential male related results including increased MWF content in a few white matter tracts, a faster decline with age of the intra- and extra-cellular water fraction and its T2 relaxation time (i.e. steeper age related negative slopes) and a faster increase in the free and quasi-free water fraction, spanning the whole grey matter. Such results point to a sexual dimorphism in brain tissue microstructure and suggest a lesser vulnerability to age-related changes in women.

The effect of second-generation antipsychotics on basal ganglia and thalamus in first-episode psychosis patients.

Patients who have recently experienced a first of episode psychosis (FEP) exhibit considerable heterogeneity in subcortical brain volumes. These results become even more divergent when exploring the effect of antipsychotic medication among other clinical and cognitive features. We aimed to contrast volumetric measures in basal ganglia and thalamus in patients with a FEP treated with different second-generation antipsychotics. T1-weighted magnetic resonance images were obtained and subcortical structures were extracted with MAGeT-Brain. Relationships with cognitive functioning were also explored with a Global Cognitive Index obtained, on average, within one month from the scan. Subgroups included: risperidone (n = 26), aripiprazole (n = 22), olanzapine (n = 19) and controls (n = 80). The olanzapine subgroup displayed significant enlargement of the right globus pallidus volume compared with all other groups. Moreover, despite not exhibiting poorer cognitive capacity than the rest of patients, results from a stepwise multiple-regression linear regression analysis identified a significant negative association between right globus pallidus volume and scores on the Global Cognitive Index among these patients. To our knowledge, this is the first study to associate treatment with olanzapine with an increase in globus pallidus volume in a sample of FEP patients with a relatively short time of antipsychotic monotherapy. Such enlargement was also found to be associated with poorer global cognitive functioning. Exploration of the biological underpinnings of this early medication-induced enlargement should be the focus of future investigations since it may lend insight towards achieving a better clinical outcome for these patients.

Verbal memory and voxel based morphometry in first episode non-affective psychosis: A process oriented approach.

OBJECTIVE: The present study aimed to comprehensively study the specific neurocognitive constructs underlying verbal memory deficits and their neuroanatomical correlates in first episode psychosis (FEP) patients. METHOD: A total of 218 FEP patients and 145 healthy participants were examined with the Rey Auditory Verbal Learning Test (a widely used verbal memory measure that provides a range of performance indexes to evaluate memory) and voxel-based morphometry (a neuroimaging analysis technique that allows investigation of focal differences in brain anatomy). RESULTS: The analyses showed that the FEP group presented significantly lower scores on acquisition/learning, F(1, 566) = 40.7; p < .001, and delayed recall, F(1, 570) = 74.12; p < .001, as well as higher rates of forgetting, F(1, 566) = 20.03; p < .001. They also exhibited a significant sensitivity to retroactive, F(1, 554) = 8.74; p = .003, but not to proactive interference. Neuroimaging analyses found significant interactions between bilateral frontal lobe morphometry and proactive interference (ρFWE = 0.023). Rate of forgetting also significantly interacted with right occipital cortex morphometry (ρFWE = 0.033). Patients with higher rates of forgetting, proactive and retroactive interference demonstrated further gray matter reductions in frontal and occipital cortical areas. CONCLUSIONS: These findings emphasize the anterior orbitofrontal cortex as the brain region that contributes to verbal memory deficits in FEP patients, and suggest specific relationships between different neuroanatomical structures and discrete verbal memory processes. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Patients with schizophrenia activate behavioural intentions facilitated by counterfactual reasoning.

METHOD: The main variables assessed were: answer to complete a target task (wrong or correctly), and percentage gain in the reaction time (RT) to complete a target task correctly depending on whether the prime was a counterfactual or a neutral-control cue. These variables were assessed in 37 patients with schizophrenia and 37 healthy controls. Potential associations with clinical status and socio-demographic characteristics were also explored. RESULTS: When a counterfactual prime was presented, the probability of giving an incorrect answer was lower for the entire sample than when a neutral prime was presented (OR 0.58; CI 95% 0.42 to 0.79), but the schizophrenia patients showed a higher probability than the controls of giving an incorrect answer (OR 3.89; CI 95% 2.0 to 7.6). Both the schizophrenia patients and the controls showed a similar percentage gain in RT to a correct answer of 8%. CONCLUSIONS: Challenging the results of previous research, our findings suggest a normal activation of behavioural intentions facilitated by CFT in schizophrenia. Nevertheless, the patients showed more difficulty than the controls with the task, adding support to the concept of CFT as a potential new target for consideration in future therapeutic approaches for this illness.

Counterfactual Reasoning in Non-psychotic First-Degree Relatives of People with Schizophrenia.

Counterfactual thinking (CFT) is a type of conditional reasoning that enables the generation of mental simulations of alternatives to past factual events. Previous research has found this cognitive feature to be disrupted in schizophrenia (Hooker et al., 2000; Contreras et al., 2016). At the same time, the study of cognitive deficits in unaffected relatives of people with schizophrenia has significantly increased, supporting its potential endophenotypic role in this disorder. Using an exploratory approach, the current study examined CFT for the first time in a sample of non-psychotic first-degree relatives of schizophrenia patients (N = 43), in comparison with schizophrenia patients (N = 54) and healthy controls (N = 44). A series of tests that assessed the "causal order effect" in CFT and the ability to generate counterfactual thoughts and counterfactually derive inferences using the Counterfactual Inference Test was completed. Associations with variables of basic and social cognition, levels of schizotypy and psychotic-like experiences in addition to clinical and socio-demographic characteristics were also explored. Findings showed that first-degree relatives generated a lower number of counterfactual thoughts than controls, and were more adept at counterfactually deriving inferences, specifically in the scenarios related to regret and to judgments of avoidance in an unusual situation. No other significant results were found. These preliminary findings suggest that non-psychotic first-degree relatives of schizophrenia patients show a subtle disruption of global counterfactual thinking compared with what is normally expected in the general population. Due to the potential impact of such deficits, new treatments targeting CFT improvement might be considered in future management strategies.

Emotional intelligence in non-psychotic first-degree relatives of people with schizophrenia.

UNLABELLED: Subtle social cognitive deficits in unaffected relatives of schizophrenia patients have received increasing attention over the last few years, supporting their potential endophenotypic role for this disorder. The current study assessed non-psychotic first-degree relatives' performance on a multidimensional measure of emotional intelligence (EI): the Mayer-Salovey-Caruso Emotional Intelligence Test 2.0 (MSCEIT). Endorsed by the National Institute of Mental Health, the MSCEIT is a valid and reliable instrument for detecting emotion-processing deficits among schizophrenia patients and people high in schizotypy. METHOD: Thirty-seven first-degree relatives, 37 schizophrenia outpatients and 37 healthy controls completed the MSCEIT, which comprises eight subscales aimed to assess the four branches of EI: Identifying, Facilitating, Understanding and Managing Emotions. Potential associations with cognitive function and schizotypy levels, measured with the Schizotypal Personality Questionnaire-Brief, were further evaluated. RESULTS: Relatives had significantly lower MSCEIT total scores than controls and also significantly lower scores on the Identifying emotions branch. Nevertheless, schizophrenia patients still had the poorest global EI performance. The strongest positive correlations were found in relatives and controls with measures of executive function, processing speed and general intelligence. A higher level of schizotypy correlated significantly with lower MSCEIT scores among controls, but not among relatives. CONCLUSIONS: Contrary to expectations in the general population, the current study observed subtle EI impairment in non-psychotic first-degree relatives of schizophrenia patients. These findings support the hypothesis that these EI deficiencies may be potential endophenotypes located between the clinical phenotype and the genetic predisposition for schizophrenia.

Counterfactual Reasoning Deficits in Schizophrenia Patients.

BACKGROUND: Counterfactual thinking is a specific type of conditional reasoning that enables the generation of mental simulations of alternatives to past factual events. Although it has been broadly studied in the general population, research on schizophrenia is still scarce. The aim of the current study was to further examine counterfactual reasoning in this illness. METHODS: Forty schizophrenia patients and 40 controls completed a series of tests that assessed the influence of the "causal order effect" on counterfactual thinking, and the ability to generate counterfactual thoughts and counterfactually derive inferences from a hypothetical situation. Socio-demographic and clinical characteristics, as well as neurocognitive variables, were also examined. RESULTS: Compared to controls, the schizophrenia patients generated fewer counterfactual thoughts when faced with a simulated scenario. The pattern of response when assessing the causality effect of the order was also different between the groups, with the patients being more frequently unable to attribute any ordering of events than the control subjects. Additionally, the schizophrenia patients showed more difficulties when deriving normative counterfactual inferences from hypothetical social situations. None of the counterfactual reasoning measures was associated to any of the cognitive functions or clinical and socio-demographic variables assessed. CONCLUSIONS: A global impairment in counterfactual thinking characterizes schizophrenia patients. Because of the potential impact of such deficits on psychosocial functioning, targeting counterfactual reasoning for improvement might be considered in future treatment approaches.

Symptomatic Remission and Counterfactual Reasoning in Schizophrenia.

Counterfactual thinking (CFT) is a type of conditional reasoning involving mental representations of alternatives to past factual events that previous preliminary research has suggested to be impaired in schizophrenia. However, despite the potential impact of these deficits on the functional outcome of these patients, studies examining the role of CFT in this disorder are still few in number. The present study aimed to extent previous results by evaluating CFT in the largest sample to date of schizophrenia patients in symptomatic remission and healthy controls. The relationship with symptomatology, illness duration, and sociodemographic characteristics was also explored. Methods: Seventy-eight schizophrenia patients and 84 healthy controls completed a series of tests that examined the generation of counterfactual thoughts, the influence of the "causal order effect," and the ability to counterfactually derive inferences by using de Counterfactual Inference Test. Results: Compared with controls, patients generated fewer counterfactual thoughts when faced with a simulated scenario. This deficit was negatively related to scores on all dimensions of the Positive and Negative Syndrome Scale-PANNS, as well as to longer illness duration. The results also showed that schizophrenia patients deviated significantly from the normative pattern when generating inferences from CFT. Conclusions: These findings reveal CFT impairment to be present in schizophrenia even when patients are in symptomatic remission. However, symptomatology and illness duration may have a negative influence on these patients' ability to generate counterfactual thoughts. The results might support the relevance of targeting CFT in future treatment approaches, although further research is needed to better describe the relationship between CFT and both symptomatology and functional outcome.