NPJ Schizophrenia最新文献

Anomalous perceptual experiences are relatively common in the general population. Evidence indicates that the key to distinguishing individuals with persistent psychotic experiences (PEs) with a need for care from those without is how they appraise their anomalous experiences. Here, we aimed to characterise the neural circuits underlying threatening and non-threatening appraisals in people with and without a need for care for PEs, respectively. A total of 48 participants, consisting of patients with psychosis spectrum disorder (clinical group, n = 16), non-need-for-care participants with PEs (non-clinical group, n = 16), and no-PE healthy control participants (n = 16), underwent functional magnetic resonance imaging while completing the Telepath task, designed to induce an anomalous perceptual experience. Appraisals of the anomalous perceptual experiences were examined, as well as functional brain responses during this window, for significant group differences. We also examined whether activation co-varied with the subjective threat appraisals reported in-task by participants. The clinical group reported elevated subjective threat appraisals compared to both the non-clinical and no-PE control groups, with no differences between the two non-clinical groups. This pattern of results was accompanied by reduced activation in the superior and inferior frontal gyri in the clinical group as compared to the non-clinical and control groups. Precuneus activation scaled with threat appraisals reported in-task. Resilience in the context of persistent anomalous experiences may be explained by intact functioning of fronto-parietal regions, and may correspond to the ability to contextualise and flexibly evaluate psychotic experiences.

Motivational deficits play a central role in disability due to negative symptoms of schizophrenia (SZ), but limited pathophysiological understanding impedes critically needed therapeutic development. We applied an fMRI Effort Discounting Task (EDT) that quantifies motivation using a neuroeconomic decision-making approach, capturing the degree to which effort requirements produce reductions in the subjective value (SV) of monetary reward. An analyzed sample of 21 individuals with SZ and 23 group-matched controls performed the EDT during fMRI. We hypothesized that ventral striatum (VS) as well as extended brain motivation circuitry would encode SV, integrating reward and effort costs. We also hypothesized that VS hypoactivation during EDT decisions would demonstrate a dimensional relationship with clinical amotivation severity, reflecting greater suppression by effort costs. As hypothesized, VS as well as a broader cortico-limbic network were activated during the EDT and this activation correlated positively with SV. In SZ, activation to task decisions was reduced selectively in VS. Greater VS reductions correlated with more severe clinical amotivation in SZ and across all participants. However, these diagnosis and amotivation effects could not be explained by the response to parametric variation in reward, effort, or model-based SV. Our findings demonstrate that VS hypofunction in schizophrenia is manifested during effort-based decisions and reflects dimensional motivation impairment. Dysfunction of VS impacting effort-based decision-making can provide a target for biomarker development to guide novel efforts to assess and treat disabling amotivation.

Cognitive impairment is an important predictor of disability in schizophrenia. Dopamine neurotransmission in cortical brain regions has been suggested to be of importance for higher-order cognitive processes. The aim of this study was to examine the relationship between extrastriatal dopamine D2-R availability and cognitive function, using positron emission tomography and the high-affinity D2-R radioligand [¹¹C]FLB 457, in an antipsychotic-naive sample of 18 first-episode psychosis patients and 16 control subjects. We observed no significant associations between D2-R binding in the dorsolateral prefrontal cortex or hippocampus (β = 0.013-0.074, partial r = -0.037-0.273, p = 0.131-0.841). Instead, using Bayesian statistics, we found moderate support for the null hypothesis of no relationship (BF_H0:H1 = 3.3-8.2). Theoretically, our findings may suggest a lack of detrimental effects of D2-R antagonist drugs on cognition in schizophrenia patients, in line with clinical observations.

Humans frequently use tools to reduce action-related efforts. Interestingly, several studies have demonstrated that individuals had tool-related biases in terms of perceived effort reduction during motor imagery tasks, despite the lack of evidence of real benefits. Reduced effort allocation has been repeatedly found in schizophrenia, but it remains unknown how schizophrenia patients perceive tool-related benefits regarding effort. Twenty-four schizophrenia patients and twenty-four nonclinical participants were instructed to move the same quantities of objects with their hands or with a tool in both real and imagined situations. Imagined and real movement durations were recorded. Similarly to nonclinical participants, patients overestimated tool-related benefits and underestimated tool-related effort in terms of time when they mentally simulated a task requiring the use of a tool. No association between movement durations and psychotic symptoms was found. Our results open new perspectives on the issue of effort in schizophrenia.

Postmortem and neuroimaging studies show low levels of cortical muscarinic M1 receptors (CHRM1) in patients with schizophrenia which is significant because CHRM signalling has been shown to change levels of gene expression and cortical gene expression is altered in schizophrenia. We decided to identify CHRM1-mediated changes in cortical gene expression by measuring levels of RNA in the cortex of the Chrm1^-/- mouse (n = 10), where there would be no signalling by that receptor, and in wild type mouse (n = 10) using the Affymetrix Mouse Exon 1.0 ST Array. We detected RNA for 15,501 annotated genes and noncoding RNA of which 1,467 RNAs were higher and 229 RNAs lower in the cortex of the Chrm1^-/- mouse. Pathways and proteins affected by the changes in cortical gene expression in the Chrm1^-/- are linked to the molecular pathology of schizophrenia. Our human cortical gene expression data showed 47 genes had altered expression in Chrm1^-/- mouse and the frontal pole from patients with schizophrenia with the change in expression of 44 genes being in opposite directions. In addition, genes with altered levels of expression in the Chrm1^-/- mouse have been shown to affect amyloid precursor protein processing which is associated with the pathophysiology of Alzheimer's disease, and 69 genes with altered expression in the Chrm1^-/- mouse are risk genes associated with human cognitive ability. Our findings argue CHRM1-mediated changes in gene expression are relevant to the pathophysiologies of schizophrenia and Alzheimer's disease and the maintenance of cognitive ability in humans.

Determining the optimal antipsychotic target dose in acute phase treatment is of high clinical relevance. The effect of antipsychotics on negative symptoms should be taken into account because patients will often continue on the treatment received in the acute phase. Therefore, we conducted a formal dose-response meta-analysis of negative symptoms and positive symptoms based on a systematic review of fixed-dose randomized controlled trials (RCTs) that examined the effectiveness of antipsychotics for the acute exacerbation of schizophrenia. Forty RCTs included a total of 15,689 patients. The 95% effective doses per day for the 13 antipsychotics included and 3 long acting were mostly different for negative and positive symptoms: amisulpride (481 mg, 690.6 mg); aripiprazole (11.9 mg, 11 mg); asenapine (7.61 mg, 5.66 mg); brexpiprazole (2.1 mg, 4 mg); cariprazine (4 mg, 6.51 mg); haloperidol (6.34 mg, 7.36 mg); lurasidone (58.2 mg, 86.3 mg); olanzapine (15.5 mg, 9.52 mg); olanzapine long-acting injection (15.7 mg, 13.5 mg); paliperidone (7.2 mg, 7 mg); paliperidone long-acting injection (7.5 mg, 5.9 mg); quetiapine instant-release (264.2 mg, 316.5 mg); quetiapine extended-release (774 mg, 707.2 mg); risperidone (7.5 mg, 7.7 mg); risperidone long-acting injection (5.13 mg, 6.7 mg); sertindole (13.5 mg, 16.3 mg); and ziprasidone (71.6 mg, 152.6 mg). The shape of the dose-response curves varied across different drugs with most drugs showing a plateau at higher doses. Most dose-response curves suggested that the near-maximum effective doses could be in the lower-to-medium range of the licensed dose. Additional RCTs are necessary to establish the optimal dose.

Automated extraction of quantitative linguistic features has the potential to predict objectively the onset and progression of psychosis. These linguistic variables are often considered to be biomarkers, with a large emphasis placed on the pathological aberrations in the biological processes that underwrite the faculty of language in psychosis. This perspective offers a reminder that human language is primarily a social device that is biologically implemented. As such, linguistic aberrations in patients with psychosis reflect both social and biological processes affecting an individual. Failure to consider the sociolinguistic aspects of NLP measures will limit their usefulness as digital tools in clinical settings. In the context of psychosis, considering language as a biosocial marker could lead to less biased and more accessible tools for patient-specific predictions in the clinic.

In order for measurement-based care to be implemented, there is a need for brief rating instruments that can be administered in a short amount of time, but that are still sufficiently informative. Here, we assessed the drug-placebo sensitivity of the six-item subscale (PANSS-6) of the 30-item Positive and Negative Syndrome Scale (PANSS-30) using a large collection of patient-level data (n = 6685) from randomized controlled trials of risperidone and paliperidone. When analyzing the data by study, we found no material difference in mean effect sizes (ES) between the two measures (PANSS-30 ES = 0.45, PANSS-6 ES = 0.44; p = 0.642). Stratifying the pooled population according to several putative effect moderators (e.g., age, formulation, dose, or diagnosis) generally yielded no meaningful ES differences between the two measures. Similarly, early improvement (≥20% improvement at week 1) on the PANSS-6 predicted subsequent response (≥40% improvement at endpoint) as well as the analog prediction using PANSS-30. Finally, cross-sectional symptom remission assessed via the PANSS-6 showed very good agreement (sensitivity = 100%, specificity = 98%) with cross-sectional symptom remission defined by the Remission in Schizophrenia Working Group.

Cognitive gains following cognitive training interventions are associated with improved functioning in people with schizophrenia (SCZ). However, considerable inter-individual variability is observed. Here, we evaluate the sensitivity of brain structural features to predict functional response to auditory-based cognitive training (ABCT) at a single-subject level. We employed whole-brain multivariate pattern analysis with support vector machine (SVM) modeling to identify gray matter (GM) patterns that predicted higher vs. lower functioning after 40 h of ABCT at the single-subject level in SCZ patients. The generalization capacity of the SVM model was evaluated by applying the original model through an out-of-sample cross-validation analysis to unseen SCZ patients from an independent validation sample who underwent 50 h of ABCT. The whole-brain GM volume-based pattern classification predicted higher vs. lower functioning at follow-up with a balanced accuracy (BAC) of 69.4% (sensitivity 72.2%, specificity 66.7%) as determined by nested cross-validation. The neuroanatomical model was generalizable to an independent cohort with a BAC of 62.1% (sensitivity 90.9%, specificity 33.3%). In particular, greater baseline GM volumes in regions within superior temporal gyrus, thalamus, anterior cingulate, and cerebellum predicted improved functioning at the single-subject level following ABCT in SCZ participants. The present findings provide a structural MRI fingerprint associated with preserved GM volumes at a single baseline timepoint, which predicted improved functioning following an ABCT intervention, and serve as a model for how to facilitate precision clinical therapies for SCZ based on imaging data, operating at the single-subject level.