Brain ageing in schizophrenia: evidence from 26 international cohorts via the ENIGMA Schizophrenia consortium.

Schizophrenia (SZ) is associated with an increased risk of life-long cognitive impairments, age-related chronic disease, and premature mortality. We investigated evidence for advanced brain ageing in adult SZ patients, and whether this was associated with clinical characteristics in a prospective meta-analytic study conducted by the ENIGMA Schizophrenia Working Group. The study included data from 26 cohorts worldwide, with a total of 2803 SZ patients (mean age 34.2 years; range 18-72 years; 67% male) and 2598 healthy controls (mean age 33.8 years, range 18-73 years, 55% male). Brain-predicted age was individually estimated using a model trained on independent data based on 68 measures of cortical thickness and surface area, 7 subcortical volumes, lateral ventricular volumes and total intracranial volume, all derived from T1-weighted brain magnetic resonance imaging (MRI) scans. Deviations from a healthy brain ageing trajectory were assessed by the difference between brain-predicted age and chronological age (brain-predicted age difference [brain-PAD]). On average, SZ patients showed a higher brain-PAD of +3.55 years (95% CI: 2.91, 4.19; I2 = 57.53%) compared to controls, after adjusting for age, sex and site (Cohen's d = 0.48). Among SZ patients, brain-PAD was not associated with specific clinical characteristics (age of onset, duration of illness, symptom severity, or antipsychotic use and dose). This large-scale collaborative study suggests advanced structural brain ageing in SZ. Longitudinal studies of SZ and a range of mental and somatic health outcomes will help to further evaluate the clinical implications of increased brain-PAD and its ability to be influenced by interventions.

Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia-related genes.

Schizophrenia has been conceived as a disorder of brain connectivity, but it is unclear how this network phenotype is related to the underlying genetics. We used morphometric similarity analysis of MRI data as a marker of interareal cortical connectivity in three prior case-control studies of psychosis: in total, n = 185 cases and n = 227 controls. Psychosis was associated with globally reduced morphometric similarity in all three studies. There was also a replicable pattern of case-control differences in regional morphometric similarity, which was significantly reduced in patients in frontal and temporal cortical areas but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in morphometric similarity was spatially correlated with cortical expression of a weighted combination of genes enriched for neurobiologically relevant ontology terms and pathways. In addition, genes that were normally overexpressed in cortical areas with reduced morphometric similarity were significantly up-regulated in three prior post mortem studies of schizophrenia. We propose that this combined analysis of neuroimaging and transcriptional data provides insight into how previously implicated genes and proteins as well as a number of unreported genes in their topological vicinity on the protein interaction network may drive structural brain network changes mediating the genetic risk of schizophrenia.

Early life Adversity, functional connectivity and cognitive performance in Schizophrenia: The mediating role of IL-6.

OBJECTIVE: Exposure to childhood trauma (CT) is associated with cognitive impairment in schizophrenia, and deficits in social cognition in particular. Here, we sought to test whether IL-6 mediated the association between CT and social cognition both directly, and sequentially via altered default mode network (DMN) connectivity. METHODS: Three-hundred-and-eleven participants (104 patients and 207 healthy participants) were included, with MRI data acquired in a subset of n = 147. CT was measured using the childhood trauma questionnaire (CTQ). IL-6 was measured in both plasma and in toll like receptor (TLR) stimulated whole blood. The CANTAB emotion recognition task (ERT) was administered to assess social cognition, and cortical connectivity was assessed based on resting DMN connectivity. RESULTS: Higher IL-6 levels, measured both in plasma and in toll-like receptor (TLR-2) stimulated blood, were significantly correlated with higher CTQ scores and lower cognitive and social cognitive function. Plasma IL-6 was further observed to partly mediate the association between higher CT scores and lower emotion recognition performance (CTQ total: ßindirect -0.0234, 95% CI: -0.0573 to -0.0074; CTQ physical neglect: ßindirect = -0.0316, 95% CI: -0.0741 to -0.0049). Finally, sequential mediation was observed between plasma IL-6 levels and DMN connectivity in mediating the effects of higher CTQ on lower social cognitive function (ßindirect = -0.0618, 95% CI: -0.1523 to -0.285). CONCLUSION: This work suggests that previous associations between CT and social cognition may be partly mediated via an increased inflammatory response. IL-6's association with changes in DMN activity further suggest at least one cortical network via which CT related effects on cognition may be transmitted.

Childhood trauma, parental bonding, and social cognition in patients with schizophrenia and healthy adults.

OBJECTIVE: This study investigated associations between childhood trauma, parental bonding, and social cognition (i.e., Theory of Mind and emotion recognition) in patients with schizophrenia and healthy adults. METHODS: Using cross-sectional data, we examined the recollections of childhood trauma experiences and social cognitive abilities in 74 patients with schizophrenia and 116 healthy adults. RESULTS: Patients had significantly higher scores compared with healthy participants on childhood trauma, and lower scores on parental bonding and social cognitive measures. Physical neglect was found to be the strongest predictor of emotion recognition impairments in both groups. Optimal parental bonding attenuated the impact of childhood trauma on emotion recognition. CONCLUSION: The present study provides evidence of an association between physical neglect and emotion recognition in patients with schizophrenia and healthy individuals and shows that both childhood trauma and parental bonding may influence social cognitive development. Psychosocial interventions should be developed to prevent and mitigate the long-term effects of childhood adversities.

Integrating machining learning and multimodal neuroimaging to detect schizophrenia at the level of the individual.

Schizophrenia is a severe psychiatric disorder associated with both structural and functional brain abnormalities. In the past few years, there has been growing interest in the application of machine learning techniques to neuroimaging data for the diagnostic and prognostic assessment of this disorder. However, the vast majority of studies published so far have used either structural or functional neuroimaging data, without accounting for the multimodal nature of the disorder. Structural MRI and resting-state functional MRI data were acquired from a total of 295 patients with schizophrenia and 452 healthy controls at five research centers. We extracted features from the data including gray matter volume, white matter volume, amplitude of low-frequency fluctuation, regional homogeneity and two connectome-wide based metrics: structural covariance matrices and functional connectivity matrices. A support vector machine classifier was trained on each dataset separately to distinguish the subjects at individual level using each of the single feature as well as their combination, and 10-fold cross-validation was used to assess the performance of the model. Functional data allow higher accuracy of classification than structural data (mean 82.75% vs. 75.84%). Within each modality, the combination of images and matrices improves performance, resulting in mean accuracies of 81.63% for structural data and 87.59% for functional data. The use of all combined structural and functional measures allows the highest accuracy of classification (90.83%). We conclude that combining multimodal measures within a single model is a promising direction for developing biologically informed diagnostic tools in schizophrenia.

Detecting schizophrenia at the level of the individual: relative diagnostic value of whole-brain images, connectome-wide functional connectivity and graph-based metrics.

BACKGROUND: Previous studies using resting-state functional neuroimaging have revealed alterations in whole-brain images, connectome-wide functional connectivity and graph-based metrics in groups of patients with schizophrenia relative to groups of healthy controls. However, it is unclear which of these measures best captures the neural correlates of this disorder at the level of the individual patient. METHODS: Here we investigated the relative diagnostic value of these measures. A total of 295 patients with schizophrenia and 452 healthy controls were investigated using resting-state functional Magnetic Resonance Imaging at five research centres. Connectome-wide functional networks were constructed by thresholding correlation matrices of 90 brain regions, and their topological properties were analyzed using graph theory-based methods. Single-subject classification was performed using three machine learning (ML) approaches associated with varying degrees of complexity and abstraction, namely logistic regression, support vector machine and deep learning technology. RESULTS: Connectome-wide functional connectivity allowed single-subject classification of patients and controls with higher accuracy (average: 81%) than both whole-brain images (average: 53%) and graph-based metrics (average: 69%). Classification based on connectome-wide functional connectivity was driven by a distributed bilateral network including the thalamus and temporal regions. CONCLUSION: These results were replicated across the three employed ML approaches. Connectome-wide functional connectivity permits differentiation of patients with schizophrenia from healthy controls at single-subject level with greater accuracy; this pattern of results is consistent with the 'dysconnectivity hypothesis' of schizophrenia, which states that the neural basis of the disorder is best understood in terms of system-level functional connectivity alterations.

Effects of complement gene-set polygenic risk score on brain volume and cortical measures in patients with psychotic disorders and healthy controls.

Multiple genome-wide association studies of schizophrenia have reported associations between genetic variants within the MHC region and disease risk, an association that has been partially accounted for by alleles of the complement component 4 (C4) gene. Following on previous findings of association between both C4 and other complement-related variants and memory function, we tested the hypothesis that polygenic scores calculated based on identified schizophrenia risk alleles within the "complement" system would be broadly associated with memory function and associated brain structure. We tested this using a polygenic risk score (PRS) calculated for complement genes, but excluding C4 variants. Higher complement-based PRS scores were observed to be associated with lower memory scores for the sample as a whole (N = 620, F change = 8.25; p = .004). A significant association between higher PRS and lower hippocampal volume was also observed (N = 216, R2 change = 0.016, p = .015). However, after correcting for further testing of association with the more general indices of cortical thickness, surface area or total brain volume, none of which were associated with complement, the association with hippocampal volume became non-significant. A post-hoc analysis of hippocampal subfields suggested an association between complement PRS and several hippocampal subfields, findings that appeared to be particularly driven by the patient sample. In conclusion, our study yielded suggestive evidence of association between complement-based schizophrenia PRS and variation in memory function and hippocampal volume.

Computerised working memory-based cognitive remediation therapy does not affect Reading the Mind in The Eyes test performance or neural activity during a Facial Emotion Recognition test in psychosis.

Working memory-based cognitive remediation therapy (CT) for psychosis has recently been associated with broad improvements in performance on untrained tasks measuring working memory, episodic memory and IQ, and changes in associated brain regions. However, it is unclear whether these improvements transfer to the domain of social cognition and neural activity related to performance on social cognitive tasks. We examined performance on the Reading the Mind in the Eyes test (Eyes test) in a large sample of participants with psychosis who underwent working memory-based CT (N = 43) compared to a control group of participants with psychosis (N = 35). In a subset of this sample, we used functional magnetic resonance imaging (fMRI) to examine changes in neural activity during a facial emotion recognition task in participants who underwent CT (N = 15) compared to a control group (N = 15). No significant effects of CT were observed on Eyes test performance or on neural activity during facial emotion recognition, either at p < 0.05 family-wise error or at a p < 0.001 uncorrected threshold, within a priori social cognitive regions of interest. This study suggests that working memory-based CT does not significantly impact an aspect of social cognition which was measured behaviourally and neurally. It provides further evidence that deficits in the ability to decode mental state from facial expressions are dissociable from working memory deficits, and suggests that future CT programmes should target social cognition in addition to working memory for the purposes of further enhancing social function.

Effects of MiR-137 genetic risk score on brain volume and cortical measures in patients with schizophrenia and controls.

Multiple genome-wide association studies of schizophrenia have implicated genetic variants within the gene encoding microRNA-137. As risk variants within or regulated by MIR137 have been implicated in memory performance, we investigated the additive effects of schizophrenia-associated risk variants in genes empirically regulated by MIR137 on brain regions associated with memory function. A polygenic risk score (PRS) was calculated (at a p = 0.05 threshold), using this empirically regulated MIR137 gene set, to investigate associations between this PRS and structural brain measures. These measures included total brain volume, cortical thickness, cortical surface area, and hippocampal volume, in a sample of 216 individuals consisting of healthy participants (n = 171) and patients with psychosis (n = 45). We did not observe a significant association between MIR137 PRS and these cortical thickness, surface area or hippocampal volume measures linked to memory function; a significant association between increasing PRS and decreasing total brain volume, independent of diagnosis status (R2 = 0.008, Beta = -0.09, p = 0.029), was observed. This did not survive correction for multiple testing. In conclusion, our study yielded only suggestive evidence that risk variants interacting with MIR137 impacts on cortical structure.

Childhood trauma is associated with altered white matter microstructural organization in schizophrenia.

It has been reported that childhood trauma (CT) is associated with reductions in fractional anisotropy (FA) in individuals with schizophrenia (SZ). Here, we hypothesized that SZ with high levels of CT will show the greatest reductions in FA in frontolimbic and frontoparietal regions compared to healthy controls (HC) with high trauma levels and participants with no/low levels of CT. Thirty-seven SZ and 129 HC with CT experience were dichotomized into groups of 'none/low' or 'high' levels. Participants underwent diffusion-weighted MRI, and Tract-based spatial statistics were employed to assess the main effect of diagnosis, main effect of CT severity irrespective of diagnosis, and interaction between diagnosis and CT severity. SZ showed FA reductions in the corpus callosum and corona radiata compared to HC. Irrespective of a diagnosis, high CT levels (n = 48) were related to FA reductions in frontolimbic and frontoparietal regions compared to those with none/low levels of CT (n = 118). However, no significant interaction between diagnosis and high levels of CT was found (n = 13). Across all participants, we observed effects of CT on late developing frontolimbic and frontoparietal regions, suggesting that the effects of CT severity on white matter organization may be independent of 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.

Bilateral anterior corona radiata microstructure organisation relates to impaired social cognition in schizophrenia.

OBJECTIVE: The Corona Radiata (CR) is a large white matter tract in the brain comprising of the anterior CR (aCR), superior CR (sCR), and posterior CR (pCR), which have associations with cognition, self-regulation, and, in schizophrenia, positive symptom severity. This study tested the hypothesis that the microstructural organisation of the aCR, as measured by Fractional Anisotropy (FA) using Diffusion Tensor Imaging (DTI), would relate to poorer social cognitive outcomes and higher positive symptom severity for people with schizophrenia, when compared to healthy participants. We further hypothesised that increased positive symptoms would relate to poorer social cognitive outcomes. METHODS: Data were derived from n = 178 healthy participants (41 % females; 36.11 ± 12.36 years) and 58 people with schizophrenia (30 % females; 42.4 ± 11.1 years). The Positive and Negative Symptom Severity Scale measured clinical symptom severity. Social Cognition was measured using the Reading the Mind in the Eyes Test (RMET) Total Score, as well as the Positive, Neutral, and Negative stimuli valence. The ENIGMA-DTI protocol tract-based spatial statistics (TBSS) was used. RESULTS: There was a significant difference in FA for the CR, in individuals with schizophrenia compared to healthy participants. On stratification, both the aCR and pCR were significantly different between groups, with patients showing reduced white matter tract microstructural organisation. Significant negative correlations were observed between positive symptomatology and reduced microstructural organisation of the aCR. Performance for RMET negative valence items was significantly correlated bilaterally with the aCR, but not the sCR or pCR, and no relationship to positive symptoms was observed. CONCLUSIONS: These data highlight specific and significant microstructural white-matter differences for people with schizophrenia, which relates to positive clinical symptomology and poorer performance on social cognition stimuli. While reduced FA is associated with higher positive symptomatology in schizophrenia, this study shows the specific associated with anterior frontal white matter tracts and reduced social cognitive performance. The aCR may have a specific role to play in frontal-disconnection syndromes, psychosis, and social cognitive profile within schizophrenia, though further research requires more sensitive, specific, and detailed consideration of social cognition outcomes.

Online learning predictors of mental health in third-level students during the COVID-19 pandemic in Ireland.

Objective COVID-19 forced third-level students to transition to online learning (OL). Many students encountered issues with OL, such as accessibility. However, the relationship between OL issues and mental health during this time remains poorly understood. Participants: Third-level students in Ireland (N = 268) completed an online questionnaire examining experiences with OL and mental health during COVID-19. Methods: OL social, lecturer, accessibility, individual skills, and environment issues, were entered into logistic regression analyses to examine whether these variables predicted mental health outcomes and/or preference to keep OL. Results: Students reporting more individual skills issues were more likely to attain a probable diagnosis of posttraumatic stress disorder, complex posttraumatic stress disorder, and depression (p < 0.0083); students who reported more environment issues were less likely to report preference to keep OL (p < 0.0005). Conclusions: Given individual skills issues associated with worse mental health, future research should examine improving student perceptions of their own OL skills.

Childhood trauma, IL-6 and weaker suppression of the default mode network (DMN) during theory of mind (ToM) performance in schizophrenia.

Background: Both low-grade systemic inflammation and functional connectivity of the default mode network (DMN) during rest have recently been observed to mediate the association between childhood trauma (CT) and behavioural performance on an emotion recognition task. Whether inflammation also mediates the association between CT and functional connectivity of the DMN during social cognitive task performance is unknown. Methods: 51 patients with schizophrenia (SZ) or schizoaffective disorder (SZA) and 176 healthy participants completed a theory of mind (ToM) task during fMRI. IL-6 was measured in plasma using ELISA. DMN connectivity was measured during performance of the fMRI ToM task. To examine DMN connectivity, we selected 4 a priori seeds of the DMN, i.e., the medial prefrontal cortex (PFC), right lateral parietal (LP), left LP, and posterior cingulate cortex (PCC) according to the Harvard-Oxford Cortical and Subcortical Atlas (http://www.cma.mgh.harvard.edu/fsl_atlas.html) as implemented in CONN. Results: Patients showed significantly increased DMN connectivity compared to healthy participants between each of the four seeds of the DMN and with other clusters in the brain. Across the entire sample, higher levels of IL-6 predicted increased connectivity between the mPFC and regions encompassing the cerebellum (<0.001 FWE). IL-6 mediated the association between physical neglect and weaker suppression of the posterior cingulate cortex (PCC) DMN seed -left precentral and postcentral gyrus (ßINDIRECT = .0170, CI: 0.0008 to.0506) connectivity during ToM performance. Discussion: This is the first study to our knowledge that provides evidence that higher plasma IL-6 mediates the association between higher childhood neglect and increased DMN connectivity during ToM task performance. Consistent with our previous study that IL-6 mediated the association between early life stress exposure and reduced connectivity of the DMN during rest, here IL-6 mediated the association between early life stress and increased connectivity of the DMN during ToM based cognitive processing. These findings suggest a biological mechanism for how chronic stress impacts social cognitive processing.

Corpus Callosum Microstructural Tract Integrity Relates to Longer Emotion Recognition Reaction Time in People with Schizophrenia.

Objective: Schizophrenia is a complex functionally debilitating neurodevelopmental disorder, with associated social cognitive impairment. Corpus Callosum (CC) white matter tracts deficits are reported for people with schizophrenia; however, few studies focus on interhemispheric processing relative to social cognition tasks. This study aimed to determine if a relationship between the CC and social cognition exists. Method: In this cross-section study, a sample of n = 178 typical controls and n = 58 people with schizophrenia completed measures of mentalising (Reading the Mind in the Eyes), emotion recognition outcome and reaction time (Emotion Recognition Test), and clinical symptoms (Positive and Negative Symptom Scale), alongside diffusion-based tract imaging. The CC and its subregions, i.e., the genu, body, and splenium were the regions of interest (ROI). Results: Reduced white matter tract integrity was observed in the CC for patients when compared to controls. Patients performed slower, and less accurately on emotion recognition tasks, which significantly and negatively correlated to the structural integrity of the CC genu. Tract integrity further significantly and negatively related to clinical symptomatology. Conclusions: People with schizophrenia have altered white matter integrity in the genu of the CC, compared to controls, which relates to cognitive deficits associated with recognising emotional stimuli accurately and quickly, and severity of clinical symptoms.

Graph Convolutional Networks Reveal Network-Level Functional Dysconnectivity in Schizophrenia.

BACKGROUND AND HYPOTHESIS: Schizophrenia is increasingly understood as a disorder of brain dysconnectivity. Recently, graph-based approaches such as graph convolutional network (GCN) have been leveraged to explore complex pairwise similarities in imaging features among brain regions, which can reveal abstract and complex relationships within brain networks. STUDY DESIGN: We used GCN to investigate topological abnormalities of functional brain networks in schizophrenia. Resting-state functional magnetic resonance imaging data were acquired from 505 individuals with schizophrenia and 907 controls across 6 sites. Whole-brain functional connectivity matrix was extracted for each individual. We examined the performance of GCN relative to support vector machine (SVM), extracted the most salient regions contributing to both classification models, investigated the topological profiles of identified salient regions, and explored correlation between nodal topological properties of each salient region and severity of symptom. STUDY RESULTS: GCN enabled nominally higher classification accuracy (85.8%) compared with SVM (80.9%). Based on the saliency map, the most discriminative brain regions were located in a distributed network including striatal areas (ie, putamen, pallidum, and caudate) and the amygdala. Significant differences in the nodal efficiency of bilateral putamen and pallidum between patients and controls and its correlations with negative symptoms were detected in post hoc analysis. CONCLUSIONS: The present study demonstrates that GCN allows classification of schizophrenia at the individual level with high accuracy, indicating a promising direction for detection of individual patients with schizophrenia. Functional topological deficits of striatal areas may represent a focal neural deficit of negative symptomatology in schizophrenia.

Knowledge, attitudes, and behaviours towards schizophrenia, bipolar disorder, and autism: a pilot study.

OBJECTIVES: Lack of knowledge and discriminatory attitudes and behaviours towards individuals with mental disorders is a worldwide problem but may be particularly damaging for young people. This pilot study examined knowledge, attitudes and behaviours towards schizophrenia, bipolar disorder and autism within a large sample of adults in Ireland, a country with the youngest population in Europe, in order to better understand public views on these groups. METHODS: In a correlational, cross-sectional design, 307 adults in Ireland over the age of 18 completed a questionnaire over Google Forms examining knowledge, attitudes and behaviours towards schizophrenia, bipolar disorder and autism. Responses to questions specifically relating to each diagnosis were compared using trimmed mean ANOVA to examine whether responses to questions differed depending on diagnosis. RESULTS: Results indicate varied knowledge, attitudes and behaviours towards these groups, but a majority believe it should be a research priority. ANOVA and post hoc tests revealed significant differences in knowledge, attitudes and behaviours towards each of schizophrenia, bipolar disorder, and autism (p < 0.005), and reported attitudes and behaviours towards schizophrenia were more negative than either bipolar disorder or autism. A majority of participants (54.8%) felt not informed enough about mental health by the media. CONCLUSIONS: In our Irish sample, type and level of stigma varies according to mental health diagnosis. Our sample also report feeling inadequately informed about mental health by the media. Thus future policy and campaigns could consider targeting individual mental health diagnoses, with a focus on increasing familiarity and knowledge.

Interleukin 6 predicts increased neural response during face processing in a sample of individuals with schizophrenia and healthy participants: A functional magnetic resonance imaging study.

BACKGROUND: Deficits in facial emotion recognition are a core feature of schizophrenia and predictive of functional outcome. Higher plasma levels of the cytokine interleukin 6 (IL-6) have recently been associated with poorer facial emotion recognition in individuals with schizophrenia and healthy participants, but the neural mechanisms affected remain poorly understood. METHODS: Forty-nine individuals with schizophrenia or schizoaffective disorder and 158 healthy participants were imaged using functional magnetic resonance imaging during a dynamic facial emotion recognition task. Plasma IL-6 was measured from blood samples taken outside the scanner. Multiple regression was used in statistical parametric mapping software to test whether higher plasma IL-6 predicted increased neural response during task performance. RESULTS: Higher plasma IL-6 predicted increased bilateral medial prefrontal response during neutral face processing compared to angry face processing in the total sample (N = 207, tmax = 5.67) and increased left insula response during angry face processing compared to neutral face processing (N = 207, tmax = 4.40) (p < 0.05, family-wise error corrected across the whole brain at the cluster level). CONCLUSIONS: These findings suggest that higher peripheral IL-6 levels predict altered neural response within brain regions involved in social cognition and emotion during facial emotion recognition. This is consistent with recent neuroimaging research on IL-6 and suggesting a possible neural mechanism by which this cytokine might affect facial emotion recognition accuracy.

Current psychosocial stress, childhood trauma and cognition in patients with schizophrenia and healthy participants.

BACKGROUND: Cognitive difficulties are experienced frequently in schizophrenia (SZ) and are strongly predictive of functional outcome. Although severity of cognitive difficulties has been robustly associated with early life adversity, whether and how they are affected by current stress is unknown. The present study investigated whether acute stress reactivity as measured by heart rate and mood changes predict cognitive performance in patients with schizophrenia and healthy individuals, and whether this is moderated by diagnosis and previous childhood trauma exposure. METHODS: One hundred and four patients with schizophrenia and 207 healthy participants were administered a battery of tasks assessing cognitive performance after psychosocial stress induction (Trier Social Stress Test; TSST). Mood states (Profile of Mood States; POMS) and heart rate were assessed at baseline, immediately before, and after the TSST. RESULTS: Both healthy participants and patients showed increases in POMS Tension and Total Mood Disturbance scores between Time Point 2 (pre-TSST) and Time Point 3 (post-TSST). These changes were not associated with variation in cognition. Although childhood trauma exposure was associated with higher stress reactivity and poorer cognitive function in all participants, childhood trauma did not moderate the association between stress reactivity and cognition. Neither was diagnosis a moderator of this relationship. DISCUSSION: These findings suggest that while chronic stress exposure explains significant variation in cognition, acute stress reactivity (measured by changes in Tension and Total Mood Disturbance) did not. In the context of broader developmental processes, we conclude that stressful events that occur earlier in development, and with greater chronicity, are likely to be more strongly associated with cognitive variation than acute transient stressors experienced in adulthood.