Psychosis and urbanicity – a review of the recent literature from epidemiology to neurourbanism

Purpose of review: Epidemiological studies associate city living with an elevated psychosis risk. Urban (social/economic) stress and exposure to environmental toxins, pollution or disease agents have been proposed to underlie this association. This review provides an update on the recent evidence (May 2017 - November 2018). Recent findings: Of 645-screened studies, 17 on: (1) urbanicity-psychosis associations in worldwide high, middle and low-income countries, (2) explanatory mechanisms, including nature exposure, social and economic stressors and genetic risk; (3) urbanicity effects on the brain and coping; and (4) urbanicity and resources, were included. The reviewed evidence revealed complex patterns of urbanicity-psychosis associations with considerable international variation within Europe and between low, middle and high-income countries worldwide. Social and economic stressors (e.g. migration, ethnic density, economic deprivation), nature exposure and access to resources could only explain part of the urbanicity effects. Risk factors differed between countries and between affective and non-affective psychosis. Summary: Urbanicity-psychosis associations are heterogeneous and driven by multiple risk and protective factors that seem to act differently in different ethnic groups and countries. Interdisciplinary research combining approaches, e.g. from experimental neuroscience and epidemiology, is needed to unravel specific urban mechanisms that in- or decrease psychosis risk

The influence of trial-by-trial feedback on trust in health, first-episode and chronic psychosis

Trust is crucial to establishing reciprocal, positive social interactions and seems to be compromised in psychosis. The trust game offers methods to assess an individual’s trust responses to trust-reciprocating, positive feedback. Various computational techniques have been implemented to measure trust responsiveness, mostly based on investments. Here, we propose a new method, focusing on feedback response. Psychosis patients show social dysfunction and reduced trust during early and more progressed illness stages. The present study inspects differences in feedback responsiveness of 102 first-episode psychosis patients (FEPs), 43 chronic psychosis patients (CPs), and 39 healthy controls (HCs) by adopting a novel assessment approach. Additionally, baseline trust, the trust exerted without any prior knowledge of the partner’s trustworthiness, and mean trust were examined. Participants performed a multi-round trust game, playing the investor role, and were paired with a computer, programmed to return at least the invested amount, representing a trustworthy partner. The new method detected group differences, more distinguished than the former methods. Contrary to our expectations, baseline trust was intact in patients. Relative to HCs, patients were less responsive to feedback, failing to integrate the positive information into their decision-making process. The magnitude of returns was not associated with increases in trust. This novel method showed promising results and confirmed patients’ deficits within the social interactional domain

The social cognitive and neural mechanisms that underlie social functioning in individuals with schizophrenia - a review

In many individuals with a diagnosis of schizophrenia social functioning is impaired across the lifespan. Social cognition has emerged as one of the possible factors that may contribute to these challenges. Neuroimaging research can give further insights into the underlying mechanisms of social (cognitive) difficulties. This review summarises the evidence on the associations between social cognition in the domains of theory of mind and emotion perception and processing, and individuals' social functioning and social skills, as well as associated neural mechanisms. Eighteen behavioural studies were conducted since the last major review and meta-analysis in the field (inclusion between 7/2017 and 1/2022). No major review has investigated the link between the neural mechanisms of social cognition and their association with social functioning in schizophrenia. Fourteen relevant studies were included (from 1/2000 to 1/2022). The findings of the behavioural studies showed that associations with social outcomes were slightly stronger for theory of mind than for emotion perception and processing. Moreover, performance in both social cognitive domains was more strongly associated with performance on social skill measures than questionnaire-based assessment of social functioning in the community. Studies on the underlying neural substrate of these associations presented mixed findings. In general, higher activation in various regions of the social brain was associated with better social functioning. The available evidence suggests some shared regions that might underlie the social cognition-social outcome link between different domains. However, due to the heterogeneity in approaches and findings, the current knowledge base will need to be expanded before firm conclusions can be drawn

Girls-Boys: An Investigation of Gender Differences in the Behavioral and Neural Mechanisms of Trust and Reciprocity in Adolescence

Background: Trust and reciprocity toward others have often been found to increase from childhood to adulthood. Gender differences in these social behaviors have been reported in adults. While adolescence is a key-period of change in social behavior, gender differences in trust and reciprocity during this developmental stage have rarely been investigated. Methods: Here we investigate age-related gender differences in trust and reciprocity (n = 100, 51 female) and associated neural mechanisms (n = 44, 20 female) in adolescents between 13 and 19 years of age. Participants played two multi-round trust games with a pre-programmed cooperative and an unfair partner. Forty-four of 100 participants completed the trust game while undergoing functional brain imaging. Results: Participants’ investments were greater toward a cooperative than unfair game partner (p < 0.01), showing sensitivity to the degree of trustworthiness. There were no gender or age or related differences in baseline trust. In repeated cooperative interactions no gender differences were found, but younger adolescents showed slightly steeper increase of investments than older adolescents. In unfair interactions, younger males reacted with stronger decrease of investments than older males. Region of interest analysis of brain areas associated with in mentalizing, reward learning, conflict processing, and cognitive control revealed gender-by-age interactions on trusting behavior in the temporo-parietal junction (TPJ) and the caudate, showing stronger influence of age in males than in females during cooperation, and the reverse in unfair interactions. Additionally, main effects of gender were found in the TPJ, with higher activation in males, and in the caudate, with females showing greater activation. Conclusion: In first interactions and during repeated cooperative interactions, adolescent males and females showed similar trusting behavior. Younger males showed stronger responses to unfairness by others. Gender-by-age interactions in specific ROIs suggest differential development in mentalizing and reward related cognitive processes. In conjunction with previous research, our findings suggest the presence of subtle gender and age-related changes in trust and cooperation that are only detectable using larger age windows

Trust and the city: Linking urban upbringing to neural mechanisms of trust in psychosis

Objective: Elevated prevalence of non-affective psychotic disorders is often found in densely populated areas. This functional magnetic resonance imaging study investigates if reduced trust, a component of impaired social functioning in patients with psychotic disorder, is associated with urban upbringing. Methods: In total, 39 patients (22 first episode and 17 clinical high risk) and 30 healthy controls, aged 16–29, performed two multi-round trust games, with a cooperative and unfair partner during functional magnetic resonance imaging scan-ning. Baseline trust was operationalized as the first investment made, and changes of trust as changes in investments made over the 20 trials during the games. Urban exposure during upbringing (0–15 years) was defined as higher urban (≥2500 inhabitants/km2) or lower urban (<2500 inhabitants/km2). Results: Patients displayed lower baseline trust (first investment) than controls, regardless of urbanicity exposure. During cooperative interactions, lower-urban patients showed increasing investments. In addition, during cooperative interactions, group-by-developmental urbanicity interactions were found in the right and left amygdalae, although for the latter only at trend level. Higher urbanicity was associated with decreased activation of the left amygdala in patients and controls during investments and with increased activation of the right and left amygdalae in patients only, during repayments. During unfair interactions, no associations of urbanicity with behavior or brain activation were found. Conclusion: Urban upbringing was unrelated to baseline trust. Associations with urbanicity were stronger for patients compared to controls, suggesting greater susceptibility to urbanicity effects during the developmental period. Higher-urban patients failed to compensate for the initial distrust specifically during repeated cooperative interactions. This finding highlights potential implications for social functioning. Urban upbringing was linked to dif-ferential amygdala activation, suggesting altered mechanisms of feedback learning, but this was not associated with trust game behavio

Benefits of Social Contact in Individuals With Psychotic Symptoms: Do Closeness of the Contact and Empathic Skills Make the Difference?

Objectives: Social contact is known to be beneficial for humans’ mental health. Individuals with psychotic symptoms (PS) tend to show poorer social and interpersonal functioning. However, in this patient population, social contact may be crucial for their mental wellbeing and treatment success. Additionally, closeness of social contact (familiar versus less familiar others), rather than only the presence or absence of social contacts, may play an important role. Empathy may heighten the beneficial effects of social/close contact on mental health, facilitating interactions. We investigated the association between social contact and closeness of contact on mental health, defined as positive symptoms, positive affect and negative affect in PS and control participants, with empathy as a moderator. Methods: Participants were 16–30 years old. Information regarding social/close contact and mental health was obtained using the experience sampling method in individuals with PS (n = 29) and healthy controls (n = 28). Empathy was measured using a self-report questionnaire. Results: Social contact was associated with higher positive affect in the total sample. Contact with close as opposed to less close others was related to better mental health: It was associated with lower positive symptoms in the PS group, and with more positive affect in the total sample. Empathy moderated the association between closeness of contact and positive affect in the total sample, in which the combination of higher levels of empathy combined with the presence of close contact was associated with higher positive affect in the total sample. However, the direct association between empathy and positive affect was not significant per group of contact. Conclusion: The results suggest that social contact, but especially contact with a close other is important for mental health outcomes: Contact with close others is beneficial for positive affect in the total sample and for positive symptoms in individuals with PS

Neural, behavioural and real-life correlates of social context sensitivity and social reward learning during interpersonal interactions in the schizophrenia spectrum

Objective Recent findings suggest that diminished processing of positive contextual information about others during interactions may contribute to social impairment in the schizophrenia spectrum (SZ). This could be due to general social context processing deficits or specific biases against positive information. We studied the impact of positive and negative social contextual information during social interactions using functional neuroimaging and probed whether these neural mechanisms were associated with reallife social functioning in SZ. Methods Patients with SZ (N=23) and controls (N=25) played three multi-round trust games during fMRI scanning, with no, positive and negative information about the counterpart’s trustworthiness, while all counterparts were programmed to behave trustworthy. The main outcome variable was the height of the shared amount in the trust game, i.e. investment, representing an indication of trust. The first investment in the game was considered to be basic trust, since no behavioural feedback was given yet. We performed region-of-interest analyses and examined the association with real-life social functioning using the Experience Sampling Method. Results Social contextual information had no effect on patients’ first investments, whereas controls made the lowest investment after negative and the highest investments after positive contextual information was provided. Over trials, patients decreased investments, suggesting reduced social reward learning, whereas controls increased investments in response to behavioural feedback in the negative context. Patients engaged the dorsolateral prefrontal cortex (dlPFC) less than controls during context presentation and showed reduced activity within the caudate during repayments. In patients, lower investments were associated with more time spent alone and social exclusion and lower caudate activation was marginally significantly associated with higher perceived social exclusion. Conclusion The failure to adapt trust to positive and negative social contexts suggests that patients have a general insensitivity to prior social information, indicating top-down processing impairments. In addition, patients show reduced sensitivity to social reward, i.e. bottom-up processing deficits. Moreover, lower trust and lower neural activation were related to lower real-life social functioning. Together, these findings indicate that improving trust and social interactions in SZ needs a multi-faceted approach that targets both mechanisms

Association of Structural Magnetic Resonance Imaging Measures With Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis:An ENIGMA Working Group Mega-analysis

IMPORTANCE The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk.OBJECTIVE To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-).DESIGN, SETTING, AND PARTICIPANTS In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020.MAIN OUTCOMES AND MEASURES Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group).RESULTS Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (rho = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (rho = 0.43; 95% CI, 0.20 to 0.61; P = .001).CONCLUSIONS AND RELEVANCE This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.Question How are brain morphometric features associated with later psychosis conversion in individuals at clinical high risk (CHR) for developing psychosis?Findings In this case-control study including 3169 participants, lower cortical thickness, but not cortical surface area or subcortical volume, was more pronounced in individuals at CHR in a manner highly consistent with thinner cortex in individuals with established psychosis. Regions that displayed lower cortical thickness in individuals at CHR who later developed a psychotic disorder additionally displayed abnormal associations with age.Meaning In this study, CHR status and later transition to psychosis was robustly associated with lower cortical thickness; abnormal age associations and specificity to cortical thickness may point to aberrant postnatal brain development in individuals at CHR, including pruning and myelination.This case-control study investigates baseline structural magnetic resonance imaging (MRI) differences between individuals at clinical high risk and healthy controls as well as between participants at clinical high risk who later developed a psychotic disorder and those who did not

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the ‘normativeness’ of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.publishedVersio

Normative modeling of brain morphometry in clinical high risk for psychosis

Importance The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)–derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z &lt; −1.96) or supranormal (z &gt; 1.96) scores. Results Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [&lt;11.42%]) and similar to that of healthy individuals (&lt;115 individuals [&lt;9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = −0.08; 95% CI, −0.13 to −0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk