Corpus callosum microstructural organization mediates the effects of physical neglect on social cognition in schizophrenia.

Exposure to early life adversity is associated with both increased risk of developing schizophrenia and poorer performance on measures of social cognitive functioning. In this study, we examined whether interleukin-6 (IL-6) and Corpus Callosum (CC) microstructure mediated the association between childhood physical neglect and social cognition. Fifty-eight patients with a diagnosis of schizophrenia were included. The CANTAB emotion recognition task (unbiased hit rate) was used to assess social cognition. We found that the microstructural organization of the CC significantly mediated the association between physical neglect and emotion recognition. Furthermore, in a sequential mediation analysis that also considered the role of inflammatory response, the association between physical neglect, and lower emotion recognition performance was sequentially mediated by higher IL-6 and lower fractional anisotropy of the CC. This mediating effect of IL-6 was only present when simultaneously considering the effects of CC microstructural organization and remained significant while controlling for the effects of sex, BMI and medication dosage (but not age). Overall, the findings suggest that the association between physical neglect and poorer emotion recognition in schizophrenia occurs, at least in part, via its association with white matter microstructure.

Genetic and inflammatory effects on childhood trauma and cognitive functioning in patients with schizophrenia and healthy participants.

Recent studies have reported a negative association between exposure to childhood trauma, including physical neglect, and cognitive functioning in patients with schizophrenia. Childhood trauma has been found to influence immune functioning, which may contribute to the risk of schizophrenia and cognitive symptoms of the disorder. In this study, we aimed to test the hypothesis that physical neglect is associated with cognitive ability, and that this association is mediated by a combined latent measure of inflammatory response, and moderated by higher genetic risk for schizophrenia. The study included 279 Irish participants, comprising 102 patients and 177 healthy participants. Structural equation modelling was used to perform mediation and moderation analyses. Inflammatory response was measured via basal plasma levels of IL-6, TNF-α, and CRP, and cognitive performance was assessed across three domains: full-scale IQ, logical memory, and the emotion recognition task. Genetic variation for schizophrenia was estimated using a genome-wide polygenic score based on genome-wide association study summary statistics. The results showed that inflammatory response mediated the association between physical neglect and all measures of cognitive functioning, and explained considerably more variance than any of the inflammatory markers alone. Furthermore, genetic risk for schizophrenia was observed to moderate the direct pathway between physical neglect and measures of non-social cognitive functioning in both patient and healthy participants. However, genetic risk did not moderate the mediated pathway associated with inflammatory response. Therefore, we conclude that the mediating role of inflammatory response and the moderating role of higher genetic risk may independently influence the association between adverse early life experiences and cognitive function in patients and healthy participants.

Counting the Toll of Inflammation on Schizophrenia-A Potential Role for Toll-like Receptors.

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that are ubiquitously expressed in the human body. They protect the brain and central nervous system from self and foreign antigens/pathogens. The immune response elicited by these receptors culminates in the release of cytokines, chemokines, and interferons causing an inflammatory response, which can be both beneficial and harmful to neurodevelopment. In addition, the detrimental effects of TLR activation have been implicated in multiple neurodegenerative diseases such as Alzheimer's, multiple sclerosis, etc. Many studies also support the theory that cytokine imbalance may be involved in schizophrenia, and a vast amount of literature showcases the deleterious effects of this imbalance on cognitive performance in the human population. In this review, we examine the current literature on TLRs, their potential role in the pathogenesis of schizophrenia, factors affecting TLR activity that contribute towards the risk of schizophrenia, and lastly, the role of TLRs and their impact on cognitive performance in schizophrenia.

Early life stress, low-grade systemic inflammation and weaker suppression of the default mode network (DMN) during face processing in Schizophrenia.

Childhood trauma (CT) is associated with lower cognitive and social cognitive function in schizophrenia. Recent evidence suggests that the relationship between CT and cognition is mediated by both low-grade systemic inflammation and reduced connectivity of the default mode network (DMN) during resting state. This study sought to test whether the same pattern of associations was observed for DMN connectivity during task based activity. Fifty-three individuals with schizophrenia (SZ) or schizoaffective disorder (SZA) and one hundred and seventy six healthy participants were recruited from the Immune Response and Social Cognition (iRELATE) project. A panel of pro-inflammatory markers that included IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNFa), and C-reactive protein (CRP), were measured in plasma using ELISA. DMN connectivity was measured during an fMRI social cognitive face processing task. Patients showed evidence of low grade systemic inflammation and significantly increased connectivity between the left lateral parietal (LLP) cortex-cerebellum and LLP-left angular gyrus compared to healthy participants. Across the entire sample, IL-6 predicted increased connectivity between LLP-cerebellum, LLP-precuneus, and mPFC-bilateral-precentral-gyri and left postcentral gyrus. In turn, and again in the entire sample, IL-6 (but no other inflammatory marker) mediated the relationship between childhood physical neglect and LLP-cerebellum. Physical neglect scores also significantly predicted the positive association between IL-6 and LLP-precuneus connectivity. This is to our knowledge the first study that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during task based activity. Consistent with our hypothesis, exposure to trauma is associated with weaker suppression of the DMN during a face processing task, and this association was mediated via increased inflammatory response. The findings may represent part of the biological mechanism by which CT and cognitive performance are related.

Anti-inflammatory effects of 2nd generation antipsychotics in patients with schizophrenia: A systematic review and meta-analysis.

BACKGROUND: Schizophrenia is a major psychiatric disorder with unknown aetiology. Recent evidence suggests a potential role for cytokines in its pathophysiology and that antipsychotic medication may alter this. While the aetiology of schizophrenia remains only partly understood, an altered immune function representing an important avenue of further discovery. In this systematic review and meta-analysis we focus on the specific effects of second generation antipsychotics risperidone and clozapine on inflammatory cytokines. METHODS: A defined systematic search of PubMed and Web of Science databases was performed to identify relevant studies published between Jan 1900 and May 2022. After screening of 2969 papers, 43 studies (27 single-arm and 8 dual-arm) were included that consisted of a total of 1421 patients with schizophrenia in the systematic review. From these, twenty studies (4 dual-arm; 678 patients) had data available on which a meta-analysis could be carried out. RESULTS: Our meta-analysis showed a significant reduction of pro-inflammatory cytokines post-risperidone treatment in the absence of a similar association with clozapine. Subgroup analyses (First episode v chronic) demonstrated that duration of illness influenced the extent of cytokine alteration; risperidone treatment produced significant cytokine changes (lowered IL-6 and TNF-α) in chronic patients but not in first-episode psychosis (FEP) patients. CONCLUSION: Varying treatment effects on cytokines can be observed by the use of different antipsychotic drugs. The cytokine alterations post-treatment are influenced by the specific antipsychotic drugs and patient status. This may explain disease progression in certain patient groups and influence therapeutic choices in the future.

The relationship between inflammatory biomarkers and cognitive dysfunction in patients with schizophrenia: A systematic review and meta-analysis.

BACKGROUND: Schizophrenia is a complex psychiatric disorder that includes positive and negative symptoms but also debilitating cognitive deficits. Current pharmacological interventions do not target these deficits. Recent evidence suggests a connection between some inflammatory markers (including C-reactive protein) and cognitive impairment, but did not address other inflammatory markers. In the current study, we try to fill the gap by focusing on the association of Interleukin-6 (IL-6), IL-1ß, Tumor Necrosis Factor-α and CRP with cognitive dysfunction. METHODS: PUBMED and Web of Science databases were searched for all studies published until July 2022. A total of 25 studies were included in an analysis of the association between cognitive performance and variation in IL-6, IL-1ß, TNF-α and CRP. RESULTS: A total of 2398 patients were included in this study. Meta-analyses results showed a significant inverse relationship between performance in five cognitive domains (attention-processing speed, executive function, working memory, verbal and visual learning and memory) and systemic IL-6, IL-1ß, TNF-α and CRP plasma levels in patients with schizophrenia. The meta-analyses results showed a significant decline in the cognitive performances with the evaluated inflammatory markers with effect sizes ranging from -0.136 to -0.181 for IL-6, -0.188 to -0.38 for TNF-α -0.372 to -0.476 for IL-1ß and - 0.168 to -0.311 for CRP. CONCLUSION: Findings from the current study shows that cognitive deficits are reflective of elevated proinflammatory biomarkers (IL-6, IL-1ß, TNF-α and CRP) levels. The results obtained indicate relatedness between inflammation and cognitive decline in patients with schizophrenia. Understanding the underlying pathways between them could have a significant impact on the disease progression and quality of life in schizophrenia patients.