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.

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.

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.

Changes in Default-Mode Network Associated With Childhood Trauma in Schizophrenia.

BACKGROUND: There is considerable evidence of dysconnectivity within the default-mode network (DMN) in schizophrenia, as measured during resting-state functional MRI (rs-fMRI). History of childhood trauma (CT) is observed at a higher frequency in schizophrenia than in the general population, but its relationship to DMN functional connectivity has yet to be investigated. METHODS: CT history and rs-fMRI data were collected in 65 individuals with schizophrenia and 132 healthy controls. Seed-based functional connectivity between each of 4 a priori defined seeds of the DMN (medial prefrontal cortex, right and left lateral parietal lobes, and the posterior cingulate cortex) and all other voxels of the brain were compared across groups. Effects of CT on functional connectivity were examined using multiple regression analyses. Where significant associations were observed, regression analyses were further used to determine whether variance in behavioral measures of Theory of Mind (ToM), previously associated with DMN recruitment, were explained by these associations. RESULTS: Seed-based analyses revealed evidence of widespread reductions in functional connectivity in patients vs controls, including between the left/right parietal lobe (LP) and multiple other regions, including the parietal operculum bilaterally. Across all subjects, increased CT scores were associated with reduced prefrontal-parietal connectivity and, in patients, with increased prefrontal-cerebellar connectivity also. These CT-associated differences in DMN connectivity also predicted variation in behavioral measures of ToM. CONCLUSIONS: These findings suggest that CT history is associated with variation in DMN connectivity during rs-fMRI in patients with schizophrenia and healthy participants, which may partly mediate associations observed between early life adversity and cognitive performance.

Childhood trauma, brain structure and emotion recognition in patients with schizophrenia and healthy participants.

Childhood trauma, and in particular physical neglect, has been repeatedly associated with lower performance on measures of social cognition (e.g. emotion recognition tasks) in both psychiatric and non-clinical populations. The neural mechanisms underpinning this association have remained unclear. Here, we investigated whether volumetric changes in three stress-sensitive regions-the amygdala, hippocampus and anterior cingulate cortex (ACC)-mediate the association between childhood trauma and emotion recognition in a healthy participant sample (N = 112) and a clinical sample of patients with schizophrenia (N = 46). Direct effects of childhood trauma, specifically physical neglect, on Emotion Recognition Task were observed in the whole sample. In healthy participants, reduced total and left ACC volumes were observed to fully mediate the association between both physical neglect and total childhood trauma score, and emotion recognition. No mediating effects of the hippocampus and amygdala volumes were observed for either group. These results suggest that reduced ACC volume may represent part of the mechanism by which early life adversity results in poorer social cognitive function. Confirmation of the causal basis of this association would highlight the importance of resilience-building interventions to mitigate the detrimental effects of childhood trauma on brain structure and function.

Early life experiences and social cognition in major psychiatric disorders: A systematic review.

OBJECTIVE: To present a systematic review of the literature on the associations between early social environment, early life adversity, and social cognition in major psychiatric disorders, including schizophrenia, bipolar disorder, borderline personality disorder, major depressive disorder and posttraumatic stress disorder. METHOD: Relevant studies were identified via electronic and manual searches of the literature and included articles written in English and published in peer-reviewed journals up to May 2018. Quality assessment was performed using the quality evaluation scale employed in previous systematic reviews. RESULTS: A total of 25 studies were included in the systematic review with the quality assessment scores ranging from 3 to 6 (out of 6). The vast majority of the studies reviewed showed a significant association between early childhood social experience, including both insecure attachment and adversity relating to neglect or abuse, and poorer social cognitive performance. CONCLUSION: We discuss these findings in the context of an attachment model, suggesting that childhood social adversity may result in poor internal working models, selective attention toward emotional stimuli and greater difficulties with emotional self-regulation. We outline some of the steps required to translate this understanding of social cognitive dysfunction in major psychiatric disorders into a target for interventions that mitigate the adverse effects of childhood maltreatment and poor parental attachment on social cognition.

Supernatural Belief Is Not Modulated by Intuitive Thinking Style or Cognitive Inhibition.

According to the Intuitive Belief Hypothesis, supernatural belief relies heavily on intuitive thinking-and decreases when analytic thinking is engaged. After pointing out various limitations in prior attempts to support this Intuitive Belief Hypothesis, we test it across three new studies using a variety of paradigms, ranging from a pilgrimage field study to a neurostimulation experiment. In all three studies, we found no relationship between intuitive or analytical thinking and supernatural belief. We conclude that it is premature to explain belief in gods as 'intuitive', and that other factors, such as socio-cultural upbringing, are likely to play a greater role in the emergence and maintenance of supernatural belief than cognitive style.