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Connections between social stress, immune dysregulation and psychosis.A virtual reality study.Childhood trauma, ethnic minority position or growing up in an urban environment increase the risk for psychosis. The social environment, combined with genetic susceptibility, is important in the development of psychosis. We examined if an altered reaction to social stress is involved. We used a virtual reality (VR) environment, a VR café. The VR café was quiet or crowded. Virtual humans had similar or different skin colour as participants and reacted in a friendly or hostile way. Participants felt more stressed and paranoid and their physiological stress levels increased in reaction to VR stressors. This reaction was similar for persons with and without a psychosis. However, as psychosis patients were more stressed to begin with, their stress levels ended up higher. In contrast, participants with a history of childhood trauma reacted stronger to social stress.We also examined a possible role for immune dysregulation. Previous studies found altered immune markers in psychosis patients and after childhood trauma. We did not find altered immune markers in our study. Immune dysregulation may occur mainly in combination with obesity. Obesity is more common in psychosis patients. However, the psychosis patients in our sample had an healthy weight on average. Our results highlight that childhood trauma and life style warrant attention in psychosis patients.

Background: Higher liability to psychosis is associated with low self-esteem and increased sensitivity to social stress. Recently, we reported a positive relation between liability to psychosis and affective and psychotic responses to social stress. This study investigated how self-esteem moderates paranoia, peak subjective distress and stress reactivity of people with different psychosis liability in response to social stressors in virtual reality.Methods: Ninety-four individuals with lower (41 siblings and 53 controls) and 75 persons with higher psychosis liability (55 with recent onset psychotic disorder and 20 at ultra-high risk for psychosis) explored five times a virtual cafe with various social stressors (crowdedness, ethnic minority status, and hostility). They rated momentary paranoia (State Social Paranoia Scale) after each experiment and subjective distress on a visual analogue scale before and after the experiments. Positive and negative self-esteem were assessed with the Self-Esteem Rating Scale.Results: Momentary paranoia, peak subjective distress, and reactivity to social stressors were associated with negative self-esteem, but not positive self-esteem. Effects of both positive and negative self-esteem on psychotic and affective stress responses, but not stress reactivity, became significantly stronger when individuals were exposed to more stressful environments. Effects of self-esteem on momentary paranoia and peak subjective distress did not differ between the high liability and low liability group. Persons with lower psychosis liability had a stronger effect of negative self-esteem on stress reactivity than persons with higher liability.Conclusions: Positive and negative self-esteem may play an important role in affective and psychotic responses to social stress. (C) 2018 Elsevier B.V. All rights reserved.

Introduction: Cognitive biases are associated with psychosis liability and paranoid ideation. This study investigated the moderating relationship between pre-existing self-reported cognitive biases and the occurrence of paranoid ideation in response to different levels of social stress in a virtual reality environment.Methods: This study included 170 participants with different levels of psychosis liability (55 recent onset psychosis, 20 ultrahigh risk for psychosis, 42 siblings of psychotic patients, and 53 controls). All participants were exposed to virtual environments with different levels of social stress. The level of experienced paranoia in the virtual environments was measured with the State Social Paranoia Scale. Cognitive biases were assessed with a self-report continuous measure. Also, cumulative number of cognitive biases was calculated using dichotomous measures of the separate biases, based on general population norm scores.Results: Higher belief inflexibility bias (Z = 2.83, P < .001), attention to threat bias (Z = 3.40, P < .001), external attribution bias (Z = 2.60, P < .001), and data-gathering bias (Z = 2.07, P < .05) were all positively associated with reported paranoid ideation in the social virtual environments. Level of paranoid response increased with number of cognitive biases present (B = 1.73, P < .001). The effect of environmental stressors on paranoid ideation was moderated by attention to threat bias (Z = 2.78, P < .01) and external attribution bias (Z = 2.75, P < .01), whereas data-gathering bias and belief inflexibility did not moderate the relationship.Conclusion: There is an additive effect of separate cognitive biases on paranoid response to social stress. The effect of social environmental stressors on paranoid ideation is further enhanced by attention to threat bias and external attribution bias.

Psychosis is a multifactorial condition arising from an interaction between genetic liability and exposure to environmental risk factors, in particular childhood trauma. Furthermore, accumulating evidence supports a role for the immune system in the aetiology of psychosis. Increased peripheral levels of pro-inflammatory cytokines and reduced neurotrophic factors are found in patients with psychosis. Childhood trauma is highly prevalent in psychosis patients and is also associated with increased pro-inflammatory cytokines and reduced neurotrophic factors. Recent studies suggest the increase in pro-inflammatory cytokines and decrease in neurotrophic factors seen in psychosis may be attributable to the effects of child maltreatment. The aim of this study was to improve understanding of the relation between childhood trauma, inflammation and psychosis. We examined separate and interaction effects of psychosis liability and childhood trauma on serum levels of BDNF, CCL-2, CRP, IFN-gamma, IGFBP2, IL-6, PDGF, SCF and TNF-alpha in 40 patients with recent onset psychosis, 13 patients at Ultra-High Risk (UHR) for psychosis, 31 unaffected siblings of psychosis patients and 41 healthy controls. Childhood trauma was assessed retrospectively with the Childhood Trauma Questionnaire (CTQ). No statistically significant effects of psychosis liability or childhood trauma on concentrations of cytokines or growth factors in peripheral blood were found, nor were there any statistically significant interaction effects of psychosis liability with childhood trauma on serum levels of cytokines and growth factors.

BackgroundChildhood trauma is associated with higher risk for mental disorders, including psychosis. Heightened sensitivity to social stress may be a mechanism. This virtual reality study tested the effect of childhood trauma on level of paranoid ideations and distress in response to social stress, in interaction with psychosis liability and level of social stress exposure.MethodSeventy-five individuals with higher psychosis liability (55 with recent onset psychotic disorder and 20 at ultra-high risk for psychosis) and 95 individuals with lower psychosis liability (42 siblings and 53 controls) were exposed to a virtual café in five experiments with 0–3 social stressors (crowded, other ethnicity and hostility). Paranoid ideation was measured after each experiment. Subjective distress was self-rated before and after experiments. Multilevel random regression analyses were used to test main effects of childhood trauma and interaction effects.ResultsChildhood trauma was more prevalent in individuals with higher psychosis liability, and was associated with higher level of (subclinical) psychotic and affective symptoms. Individuals with a history of childhood trauma responded with more subjective distress to virtual social stress exposures. The effects of childhood trauma on paranoia and subjective distress were significantly stronger when the number of virtual environmental stressors increased. Higher psychosis liability increased the effect of childhood trauma on peak subjective distress and stress reactivity during experiments.ConclusionsChildhood trauma is associated with heightened social stress sensitivity and may contribute to psychotic and affective dysregulation later in life, through a sensitized paranoid and stress response to social stressors.

Background: A growing body of evidence supports a role for immune alterations in Schizophrenia Spectrum Disorders (SSD). A high prevalence (25-40%) of SSD has been found in patients with 22q11.2 deletion syndrome (22q11.2DS), which is known for T-cell deficits due to thymus hypoplasia. This study is the first to explore the association between the T-cell subsets and psychotic symptoms in adults with 22q11.2DS.Methods: 34 individuals (aged 19-38 yrs.) with 22q11.2DS and 34 healthy age- and gender matched control individuals were included. FACS analysis of the blood samples was performed to define T-cell subsets. Ultra-high risk for psychosis or diagnosis of SSD was determined based on CAARMS interviews and DSM-5 criteria for SSD. Positive psychotic symptom severity was measured based on the PANSS positive symptoms subscale.Results: A partial T-cell immune deficiency in 22q11.2DS patients was confirmed by significantly reduced percentages of circulating T and T-helper cells. Significantly higher percentages of inflammatory Th1, Th17, and memory T-helper cells were found in adults with 22q11.2DS. Most importantly an increased Th17 percentage was found in adults with psychotic symptoms as compared to non-psychotic adults with 22q11.2DS, and Th17 percentage were related to the presence of positive psychotic symptoms.Conclusions: Given the literature on the role of T cells and in particular of Th17 cells and IL-17 in hippocampus development, cognition and behavior, these results support the hypothesis for a role of Th17 cells in the development and/or regulation of psychotic symptoms in 22q11.2DS. This pilot study underlines the importance to further study the role of T-cell defects and of Th17 cells in the development of psychiatric symptoms. It also supports the possibility to use 22q11.2DS as a model to study T-cell involvement in the development of SSD. (C) 2018 Elsevier Inc. All rights reserved.

BACKGROUND: Psychotic disorders are characterized by a deranged immune system, including altered number and function of Natural Killer (NK) and T cells. Psychotic disorders arise from an interaction between genetic vulnerability and exposure to environmental risk factors. Exposure to social adversity during early life is particularly relevant to psychosis risk and is thought to increase reactivity to subsequent minor daily social stressors. Virtual reality allows controlled experimental exposure to virtual social stressors.AIM: To investigate the interplay between social adversity during early life, cell numbers of NK cells and T helper subsets and social stress reactivity in relation to psychosis liability.METHODS: Circulating numbers of Th1, Th2, Th17, T regulator and NK cells were determined using flow cytometry in 80 participants with low psychosis liability (46 healthy controls and 34 siblings) and 53 participants with high psychosis liability (14 ultra-high risk (UHR) patients and 39 recent-onset psychosis patients), with and without the experience of childhood trauma. We examined if cell numbers predicted subjective stress when participants were exposed to social stressors (crowdedness, hostility and being part of an ethnic minority) in a virtual reality environment.RESULTS: There were no significant group differences in Th1, Th2, Th17, T regulator and NK cell numbers between groups with a high or low liability for psychosis. However, in the high psychosis liability group, childhood trauma was associated with increased Th17 cell numbers (p = 0.028). Moreover, in the high psychosis liability group increased T regulator and decreased NK cell numbers predicted stress experience during exposure to virtual social stressors (p = 0.015 and p = 0.009 for T regulator and NK cells, respectively).CONCLUSION: A deranged Th17/T regulator balance and a reduced NK cell number are associated intermediate biological factors in the relation childhood trauma, psychosis liability and social stress reactivity.

The impact of social environments on mental states is difficult to assess, limiting the understanding of which aspects of the social environment contribute to the onset of psychotic symptoms and how individual characteristics moderate this outcome. This study aimed to test sensitivity to environmental social stress as a mechanism of psychosis using Virtual Reality (VR) experiments. Fifty-five patients with recent onset psychotic disorder, 20 patients at ultra high risk for psychosis, 42 siblings of patients with psychosis, and 53 controls walked 5 times in a virtual bar with different levels of environmental social stress. Virtual social stressors were population density, ethnic density and hostility. Paranoia about virtual humans and subjective distress in response to virtual social stress exposures were measured with State Social Paranoia Scale (SSPS) and self-rated momentary subjective distress (SUD), respectively. Pre-existing (subclinical) symptoms were assessed with the Community Assessment of Psychic Experiences (CAPE), Green Paranoid Thoughts Scale (GPTS) and the Social Interaction Anxiety Scale (SIAS). Paranoia and subjective distress increased with degree of social stress in the environment. Psychosis liability and pre-existing symptoms, in particular negative affect, positively impacted the level of paranoia and distress in response to social stress. These results provide experimental evidence that heightened sensitivity to environmental social stress may play an important role in the onset and course of psychosis.

Background: Social stressors are associated with an increased risk of psychosis. Stress sensitisation is thought to be an underlying mechanismand may be reflected in an altered autonomic stress response. Using an experimental Virtual Reality design, the autonomic stress response to social stressorswas examined in participantswith different liability to psychosis.Method: Fifty-five patients with recent onset psychotic disorder, 20 patients at ultra-high risk for psychosis, 42 siblings of patientswith psychosis and 53 controls were exposed to social stressors (crowdedness, ethnicminority status and hostility) in a Virtual Reality environment. Heart rate variability parameters and skin conductance levels were measured at baseline and during Virtual Reality experiments.Results: High psychosis liability groups had significantly increased heart rate and decreased heart rate variability compared to low liability groups both at baseline and during Virtual Reality experiments. Both low frequency (LF) and high frequency (HF) power were reduced, while the LF/HF ratiowas similar between groups. The number of virtual social stressors significantly affected heart rate, HF, LF/HF and skin conductance level. There was no interaction between psychosis liability and amount of virtual social stress.Conclusion: High liability to psychosis is associated with decreased parasympathetic activity in virtual social environments, which reflects generally high levels of arousal, rather than increased autonomic reactivity to social stressors. (C) 2016 Elsevier B.V. All rights reserved.

A large number of patients with a psychotic disorder live a life of limited participation in society, even if their psychotic symptoms have been treated successfully. An important factor in sustaining social isolation is that when social anxiety and distrust increase, the patient has learned to flee the situation and as a consequence experiences a reduction in anxiety. In this study we study the use of Virtual Reality Exposure Therapy (VRET) to enhance social participation and wellbeing for patients suffering from a psychotic disorder and social withdrawal. The study design is a single blind RCT with three-month follow-up. The VRET.P treatment consists of sixteen treatment sessions of sixty minutes each, within an eight-week timeframe. Social participation was measured by the PsyMate Experience Sampling Method before and at end of treatment, and at three-month follow-up. One hundred and sixteen participants were included in the study. Fifty-eight participants received the VRET.P treatment right away. The other fiftyeight participants received treatment as usual during the study, and were offered the VRET.P treatment after the follow-up measurement. We have finished data collection for the study; the last follow-up measurements have taken place in December 2015. We will be able to present the results of the study in June 2016 on the conference. Clinical implications and limitations of the results and the study will be discussed.

Cardiovascular disease (CVD) is the leading cause of death in modern society. Interestingly, the risk of developing CVD varies between different ethnic groups. A particularly high risk is faced by South Asians, representing over one-fifth of the world's population. Here, we review potential factors contributing to the increased cardiovascular risk in the South Asian population and discuss novel therapeutic strategies based on recent insights. In South Asians, classical ('metabolic') risk factors associated with CVD are highly prevalent and include central obesity, insulin resistance, type 2 diabetes, and dyslipidemia. A contributing factor that may underlie the development of this disadvantageous metabolic phenotype is the presence of a lower amount of brown adipose tissue (BAT) in South Asian subjects, resulting in lower energy expenditure and lower lipid oxidation and glucose uptake. As it has been established that the increased prevalence of classical risk factors in South Asians cannot fully explain their increased risk for CVD, other non-classical risk factors must underlie this residual risk. In South Asians, the prevalence of "inflammatory" risk factors including visceral adipose tissue inflammation, endothelial dysfunction, and HDL dysfunction are higher compared with Caucasians. We conclude that a potential novel therapy to lower CVD risk in the South Asian population is to enhance BAT volume or its activity in order to diminish classical risk factors. Furthermore, anti-inflammatory therapy may lower non-classical risk factors in this population and the combination of both strategies may be especially effective.

Background: Psychotic syndromes can be understood as disorders of adaptation to social context. It is not clear, however, how symptoms of psychosis develop in the daily social environment, in interaction with individual liability. Virtual Reality (VR) technology may help to investigate relationships between environment and psychosis, as it allows controlled exposure to various social risk environments. Methods: Four groups (total N=54) with different liability to psychosis (patients with first episode psychosis (FEP), siblings, ultra high risk individuals (UHR) and healthy controls) were exposed to virtual social environments. Psychological and physiological responses were measured repeatedly. The virtual environment was varied with regard to social stressors (population density, ethnic density and hostility of avatars). Results: Paranoid thoughts and social anxiety in real life correlated significantly with paranoid thoughts about avatars and subjective distress in virtual social stress environments (Spearman's correlation coefficients 0.4 0.5, p

Self-reactive B lymphocytes contribute to type 1 diabetes pathogenesis as APC and auto-Ab producers in NOD mice and humans. To shed light on the mechanisms responsible for the breakdown in B-lymphocyte self-tolerance to β-cell Ag, we utilised a model whereby hen-egg lysozyme (HEL)-specific Ig Tg (IgHEL-Tg)-Tg B lymphocytes were allowed to develop in or were transferred into mice expressing the HEL Tg under an insulin promoter (insHEL-Tg). IgHEL-Tg B lymphocytes enhanced type 1 diabetes susceptibility of insHEL-Tg NOD mice. A comparison of the tolerogenic activity of IgHEL-Tg B lymphocytes with NOD and non-autoimmune-prone C57BL/6 genetic backgrounds showed that both were rendered anergic in the presence of insHEL when competing with polyclonal B lymphocytes. Nevertheless, NOD IgHEL-Tg B lymphocytes transferred into insHEL-Tg mice were more readily susceptible to rescue from anergy than their C57BL/6 counterparts, following provision of in vivo T-cell help. The different tolerogenic outcomes were an intrinsic property of B lymphocytes rather than being related to the quality of T-cell help, with the defective response being at least partially controlled by genes mapping to insulin-dependent diabetes (Idd) susceptibility loci on Chromosome 1 (Idd5) and 4 (Idd9/11).