Identifying cognitive remediation change through computational modelling - Effects on reinforcement learning in schizophrenia

Objective: Converging research suggests that individuals with schizophrenia show a marked impairment in reinforcement learning, particularly in tasks requiring flexibility and adaptation. The problem has been associated with dopamine reward systems. This study explores, for the first time, the characteristics of this impairment and how it is affected by a behavioral intervention—cognitive remediation. Method: Using computational modelling, 3 reinforcement learning parameters based on the Wisconsin Card Sorting Test (WCST) trial-by-trial performance were estimated: R (reward sensitivity), P (punishment sensitivity), and D (choice consistency). In Study 1 the parameters were compared between a group of individuals with schizophrenia (n = 100) and a healthy control group (n = 50). In Study 2 the effect of cognitive remediation therapy (CRT) on these parameters was assessed in 2 groups of individuals with schizophrenia, one receiving CRT (n = 37) and the other receiving treatment as usual (TAU, n = 34). Results: In Study 1 individuals with schizophrenia showed impairment in the R and P parameters compared with healthy controls. Study 2 demonstrated that sensitivity to negative feedback (P) and reward (R) improved in the CRT group after therapy compared with the TAU group. R and P parameter change correlated with WCST outputs. Improvements in R and P after CRT were associated with working memory gains and reduction of negative symptoms, respectively. Conclusion: Schizophrenia reinforcement learning difficulties negatively influence performance in shift learning tasks. CRT can improve sensitivity to reward and punishment. Identifying parameters that show change may be useful in experimental medicine studies to identify cognitive domains susceptible to improvement

SAA drives proinflammatory heterotypic macrophage differentiation in the lung via CSF-1R-dependent signaling

Serum amyloid A (SAA) is expressed locally in chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD), where macrophages that do not accord with the classic M1/M2 paradigm also accumulate. In this study, the role of SAA in regulating macrophage differentiation was investigated in vitro using human blood monocytes from healthy subjects and patients with COPD and in vivo using an airway SAA challenge model in BALB/c mice. Differentiation of human monocytes with SAA stimulated the proinflammatory monokines IL-6 and IL-1β concurrently with the M2 markers CD163 and IL-10. Furthermore, SAA-differentiated macrophages stimulated with lipopolysaccharide (LPS) expressed markedly higher levels of IL-6 and IL-1β. The ALX/FPR2 antagonist WRW4 reduced IL-6 and IL-1β expression but did not significantly inhibit phagocytic and efferocytic activity. In vivo, SAA administration induced the development of a CD11chighCD11bhigh macrophage population that generated higher levels of IL-6, IL-1β, and G-CSF following ex vivo LPS challenge. Blocking CSF-1R signaling effectively reduced the number of CD11chighCD11bhigh macrophages by 71% and also markedly inhibited neutrophilic inflammation by 80%. In conclusion, our findings suggest that SAA can promote a distinct CD11chighCD11bhigh macrophage phenotype, and targeting this population may provide a novel approach to treating chronic inflammatory conditions associated with persistent SAA expression.-Anthony, D., McQualter, J. L., Bishara, M., Lim, E. X., Yatmaz, S., Seow, H. J., Hansen, M., Thompson, M., Hamilton, J. A., Irving, L. B., Levy, B. D., Vlahos, R., Anderson, G. P., Bozinovski, S. SAA drives proinflammatory heterotypic macrophage differentiation in the lung via CSF-1R-dependent signaling