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Background The development of adverse clinical outcomes in psychosis has been associated with behavioral and neuroanatomical changes related to emotional processing (Aleman & Kahn, 2005; Philips & Seidman, 2008). However, the relationship between emotional processing deficits and neuroanatomy in subjects at clinical high risk of psychosis (CHR), and their relationship to longitudinal outcomes, remains unclear. The primary aim of the present study was to investigate the association between facial emotional recognition and grey matter volume (GMV) in a large cohort of CHR individuals compared to healthy controls, and their relationship with subsequent clinical outcomes. Methods Structural imaging scans at 3T and a computer-based measure of emotional processing (Degraded Facial Affect Recognition task, DFAR), were collected at baseline from 53 healthy controls (mean age: 23.3 SD ± 3.9; 52.8% male) and 213 CHR subjects (mean age: 22.9 SD ± 4.7; 50.7% male) participating in the multi-centre EU-GEI study (data pooled from 9 sites). CHR subjects were then clinically monitored for 12 months and clinical outcomes were assessed in terms of transition/non-transition to psychosis (CAARMS criteria) and the level of overall functioning (Global Assessment of Function scale; GAF). Structural images were preprocessed with voxel-based morphometry in SPM12. DFAR performance (total, happy, angry, fear and anger) was analyzed with repeated measures ANOVA at baseline (HC/CHR as between-group factor and DFAR as within-subject factor, adjusted for age, gender, IQ and site); and with binary logistic regression at the 12-month follow-up point (adjusting for the same variables). One-way ANOVAs in SPM12 were specified to examine interactions between group status (HC/CHR, CHR-T/CHR-NT, CHR-GO/CHR/PO) and DFAR performance (total, happy, angry, fear and anger), adjusting for the same variables. Statistical inferences were made at p<.05 after voxel-wise FWE correction within four pre-defined anatomical regions of interest (ROI: amygdala, hippocampus, insula, anterior cingulate cortex/medial prefrontal cortex -ACC/MPFC-). Results At baseline, DFAR performance did not differ between HC and CHR groups and was not significantly associated with GMV in our ROIs. At the 12-month follow-up point, 39 CHR subjects showed good overall functioning (GAF≥65), whereas 93 CHR subjects had a poor functional outcome (GAF score<65); 44 CHR subjects developed a psychotic disorder and 169 did not. Compared to subjects with a good functional outcome, CHR subjects with poor overall functioning showed exacerbated recognition of angry facial emotion (p=.030), decreased GMV in ACC and hippocampus (both p=.033 FWE), and a significantly different (inverse) association between angry facial emotion recognition and hippocampal volume compared to CHR subjects with good functioning (p=.037 FWE). CHR subjects who developed psychosis did not show significant differences in DFAR performance or significant associations between DFAR and GMV compared with CHR subjects who did not become psychotic. Discussion These findings indicate that adverse global functional outcomes in people at CHR of psychosis (but not transition to psychosis) are associated with baseline deficits in the recognition of angry facial emotion, which are in turn directly related to hippocampal volume decreases compared to CHR subjects with good functional outcomes. This has implications not only for stratification of CHR subjects according to baseline behavioral and volumetric characteristics, but also suggest potential preventative avenues for poorer outcomes focused on social cognitive and emotional processes. [ABSTRACT FROM AUTHOR]

We recently reported that resting hippocampal, basal ganglia and midbrain perfusion is elevated in people at ultra high risk (UHR) for psychosis. The present study sought to replicate our previous finding in an independent UHR cohort, and examined the relationship between resting perfusion in these regions, psychosis and depression symptoms, and traumatic experiences in childhood. Pseudo-Continuous Arterial Spin Labelling (p-CASL) imaging was used to measure resting cerebral blood flow (rCBF) in 77 UHR for psychosis individuals and 25 healthy volunteers in a case-control design. UHR participants were recruited from clinical early detection services at 3 sites in the South of England. Symptoms levels were assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS), the Hamilton Depression Scale (HAM-D), and childhood trauma was assessed retrospectively using the Childhood Trauma Questionnaire (CTQ). Right hippocampal and basal ganglia rCBF were significantly increased in UHR subjects compared to controls, partially replicating our previous finding in an independent cohort. In UHR participants, positive symptoms were positively correlated with rCBF in the right pallidum. CTQ scores were positively correlated with rCBF values in the bilateral hippocampus and negatively associated with rCBF in the left prefrontal cortex. Elevated resting hippocampal and basal ganglia activity appears to be a consistent finding in individuals at high risk for psychosis, consistent with data from preclinical models of the disorder. The association with childhood trauma suggests that its influence on the risk of psychosis may be mediated through an effect on hippocampal function.

Recent years have seen considerable progress in epidemiological and molecular genetic research into environmental and genetic factors in schizophrenia, but methodological uncertainties remain with regard to validating environmental exposures, and the population risk conferred by individual molecular genetic variants is small. There are now also a limited number of studies that have investigated molecular genetic candidate gene-environment interactions (G × E), however, so far, thorough replication of findings is rare and G × E research still faces several conceptual and methodological challenges. In this article, we aim to review these recent developments and illustrate how integrated, large-scale investigations may overcome contemporary challenges in G × E research, drawing on the example of a large, international, multi-center study into the identification and translational application of G × E in schizophrenia. While such investigations are now well underway, new challenges emerge for G × E research from late-breaking evidence that genetic variation and environmental exposures are, to a significant degree, shared across a range of psychiatric disorders, with potential overlap in phenotype., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)