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Evidence suggests that early trauma may have a negative effect on cognitive functioning in individuals with psychosis, yet the relationship between childhood trauma and cognition among those at clinical high risk (CHR) for psychosis remains unexplored. Our sample consisted of 626 CHR children and 279 healthy controls who were recruited as part of the North American Prodrome Longitudinal Study 2. Childhood trauma up to the age of 16 (psychological, physical, and sexual abuse, emotional neglect, and bullying) was assessed by using the Childhood Trauma and Abuse Scale. Multiple domains of cognition were measured at baseline and at the time of psychosis conversion, using standardized assessments. In the CHR group, there was a trend for better performance in individuals who reported a history of multiple types of childhood trauma compared with those with no/one type of trauma (Cohen d = 0.16). A history of multiple trauma types was not associated with greater cognitive change in CHR converters over time. Our findings tentatively suggest there may be different mechanisms that lead to CHR states. Individuals who are at clinical high risk who have experienced multiple types of childhood trauma may have more typically developing premorbid cognitive functioning than those who reported minimal trauma do. Further research is needed to unravel the complexity of factors underlying the development of at-risk states.

Aim: Childhood Adversity (CA) is strongly linked to psychotic-like symptoms across the clinical spectrum, though the mechanisms underlying these associations remain poorly understood. Negative cognitive schemas are associated with both CA exposure and psychotic symptoms, highlighting the possibility that cognitive schemas may be a key risk pathway. The purpose of this study was to determine whether negative cognitive schemas mediate the association between CA and specific attenuated psychotic symptoms in a large sample of clinical-high risk youth. Given the variability in experiences that encompass CA (eg, abuse, neglect and poverty) and attenuated psychotic symptoms (eg, suspiciousness and perceptual abnormalities), we also tested whether these associations differ by CA type (threat vs deprivation) and attenuated positive psychotic symptom domain. Methods: Data were collected from 531 clinical-high risk youth between 12 and 35 years of age (mean = 18.80, SD = 4.21) who completed a clinical assessment that included the Structured Interview of Prodromal Syndromes (SIPS), Childhood Trauma and Abuse scale and questionnaires on cognitive schemas and depressive symptoms. Results: No direct effects of threat or deprivation exposure on any of the psychotic symptom domains were found. However, there was a unique indirect effect of threat, but not deprivation, on delusional thinking and suspiciousness through negative cognitive schemas about others. Conclusion: Cognitive vulnerability in the form of negative schemas about others may be one mechanism linking childhood threat experiences and attenuated psychotic symptoms. The results underscore the importance of targeting negative schemas in interventions to mitigate psychosis risk.

Background: While an established clinical outcome of high importance, social functioning has been emerging as possibly having a broader significance to the evolution of psychosis and long term disability. In the current study we explored the association between social decline, conversion to psychosis, and functional outcome in individuals at clinical high risk (CHR) for psychosis. Methods: 585 subjects collected in the North American Prodrome Longitudinal Study (NAPLS2) were divided into 236 Healthy Controls (HCs), and CHR subjects that developed psychosis (CHR + C, N = 79), or those that did not (Non-Converters, CHR-NC, N = 270). CHR + C subjects were further divided into those that experienced an atypical decline in social functioning prior to baseline (beyond typical impairment levels) when in min-to-late adolescence (CHR + C-SD, N = 39) or those that did not undergoing a decline (CHR + C-NSD, N = 40). Results: Patterns of poor functional outcomes varied across the CHR subgroups: CHR-NC (Poor Social 36.3%, Role 42.2%) through CHR + C-NSD (Poor Social 50%, Poor Role 67.5%) to CHR + C-SD (Poor Social 76.9%, Poor Role 89.7%) functioning. The two Converter subgroups had comparable positive symptoms at baseline. At 12 months, the CHR + C-SD group stabilized, but social functioning levels remained significantly lower than the other two subgroups. Conclusions: The current study demonstrates that pre-baseline social decline in mid-to-late adolescence predicts psychosis. In addition, we found that this social decline in converters is strongly associated with especially poor functional outcome and overall poorer prognosis. Role functioning, in contrast, has not shown similar predictor potential, and rather appears to be an illness indicator that worsens over time.

Childhood adversity is among the strongest risk factors for psychosis-spectrum disorders, though the nature and specificity of the biological mechanisms underlying this association remains unclear. Previous research reveals overlaps in the volumetric alterations observed in both adversity-exposed individuals and in psychosis-spectrum populations, highlighting the possibility that deviations in corticolimbic gray matter development may be one mechanism linking adversity and psychosis. Given that childhood adversity encompasses a wide range of adverse experiences, there is also a critical need to examine whether these different types of experiences have unique effects on corticolimbic regions. This study examined the association between childhood adversity and cortical, hippocampal, and amygdalar volume in a large sample of youth at clinical-high risk (CHR) for psychosis. We utilized a novel differentiated adversity approach that distinguishes exposures along dimensions of threat (e.g., abuse) and deprivation (e.g., poverty, neglect) to test for differential associations. Participants were drawn from the North American Prodromal Longitudinal Study (NAPLS) and completed an MRI scan and a retrospective assessment of childhood adversity at baseline. We found that deprivation exposure, but not threat, was uniquely associated with smaller cortical volume and smaller right hippocampal volume in CHR youth. These associations were masked in a generalized risk model that utilized a total adversity score. The findings suggest that deprivation exposures during childhood contribute to the subtle volumetric reductions observed in clinical high-risk samples and highlight the importance of disentangling different dimensions of adversity.

Purpose: Estrogen or 17β-estradiol (17β-E2) is known to act as an antioxidant and has neuroprotective effects. The purpose of this study is to evaluate the effects of estrogen and estrogen receptor beta (ERβ) on photoreceptor cell structure and function in an experimental model for light-induced photoreceptor degeneration. Methods: 3-5 months old Balb/c mice were exposed to constant light of ~1500 lux. Mice were divided into four groups and treated via intraperitoneal injections with vehicle, 17β-E2, the ERβ inhibitor [4-(2-phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3-yl)phenol, (PHTPP), or a combination of 17β-E2 and PHTPP. Retinal function was evaluated by electroretinogram (ERG), and eyes were assessed by histology and immunohistochemistry. Results: Light damage resulted in a loss of the number of photoreceptor nuclei in the outer nuclear layer (ONL), a loss of UV cone opsin immunoreactivity and a reduction in rod- and cone-mediated ERG signals. 17β-E2 treatment significantly increased the ONL cell count and increased the rod-driven a-wave in the ERG. PHTPP alone had no effect, but PHTPP eliminated the protective effect of exogenously applied estrogen. Likewise, 17β-E2 significantly increased the amount of UV cone opsin immunoreactivity, an effect that was negated by co-administration of PHTPP. Conclusions: Estrogen supplementation was found to reduce rod and cone photoreceptor cell damage in this light-induced photoreceptor degeneration mouse model, an effect that was mediated via ERβ activation.

Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%-67%), Verbal Ability (43%-72%), Visuospatial Ability (20%-80%), and Attention/Processing Speed (28%-74%), while the lowest heritability was observed for Executive Function (20%-40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average r g = '.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population.