Reduced hippocampal volume (HV) is an established brain morphological feature of psychiatric conditions. HV is associated with brain connectivity in humans and non-human animals and altered connectivity is associated with risk for psychiatric illness. Associations between HV and connectivity remain poorly characterized in humans, and especially in phases of psychiatric illness that precede disease onset. This study examined associations between HV and hippocampal functional connectivity (FC) during rest in 141 healthy controls and 248 individuals at-risk for psychosis. Significant inverse associations between HV and hippocampal FC with the inferior parietal lobe (IPL) and thalamus were observed. Select associations between hippocampal FC and HV were moderated by diagnostic group. Significant moderation results shifted from implicating the IPL to the temporal pole after excluding participants on antipsychotic medication. Considered together, this work implicates hippocampal FC with the temporoparietal junction, within a specialized subsystem of the default mode network, as sensitive to HV.

Aim: individuals at clinical high risk (CHR) for psychosis have been shown to experience more trauma than the general population. However, although the effects of trauma appear to impact some symptoms it does not seem to increase the risk of transition to psychosis. The aim of this paper was to examine the prevalence of trauma, and its association with longitudinal clinical and functional outcomes in a large sample of CHR individuals. Methods: From the North American Prodrome Longitudinal Study-3 (NAPLS-3) 690 CHR individuals and 91 healthy controls from nine study sites between 2015–2018 were assessed. Historical trauma experiences were captured at baseline. Participants completed longitudinal assessments measuring clinical outcomes including positive and negative symptoms, depression, social and role functioning and assessing transition to psychosis. Results: From the 690 CHR participants and 9 6 healthy controls, 343 (49.6%) and 15 (15.6%), respectively, reported a history of trauma (p<0.001). Emotional neglect (70.3%) was the most commonly reported type of trauma, followed by psychological abuse (57.4%). Among CHR participants, time to transition to psychosis was not associated with trauma. Baseline depression and suspiciousness/persecutory ideas were statistically significantly different between CHR individuals who did or did not experience trauma. However, when examining clinical and functional outcomes over 12-months of follow-up, there were no differences between those who experienced trauma and those who did not. Conclusion: Overall, trauma is a significantly prevalent among CHR individuals. The effects of trauma on transition and longitudinal clinical and functional outcomes were not significant.

Introduction: Paranoia is a common and impairing psychosis symptom, which exists along a severity continuum that extends into the general population. Individuals at clinical high-risk for psychosis (CHR) frequently experience paranoia and this may elevate their risk for developing full psychosis. Nonetheless, limited work has examined the efficient measurement of paranoia in CHR individuals. The present study aimed to validate an often used self-report measure, the Revised Green Paranoid Thoughts Scale (RGPTS), in this critical population. Method: Participants were CHR individuals (n = 103), mixed clinical controls (n = 80), and healthy controls (n = 71) who completed self-report and interview measures. Confirmatory factor analysis (CFA), psychometric indices, group differences, and relations to external measures were used to evaluate the reliability and validity of the RGPTS. Results: CFA replicated a two-factor structure for the RGPTS and the associated Reference and Persecution scales were reliable. CHR individuals scored significantly higher on both Reference and Persecution, relative to both healthy (ds = 1.03, .86) and clinical controls (ds = .64, .73). In CHR participants, correlations between Reference and Persecution and external measures were smaller than expected, though showed evidence of discriminant validity (e.g., interviewer-rated paranoia, r = .24). When examined in the full sample, correlation magnitude was larger and follow-up analyses indicated that Reference related most specifically to paranoia (β = .32), whereas Persecution uniquely related to poor social functioning (β = −.29). Conclusion: These results demonstrate the reliability and validity of the RGPTS, though its scales related more weakly to severity in CHR individuals. The RGPTS may be useful in future work aiming to develop symptom-specific models of emerging paranoia in CHR individuals.

There is inconsistent evidence for increased stress exposure among individuals at clinical high risk (CHR) for psychosis. Yet similar to patients with a diagnosed psychotic illness, the preponderance of evidence suggests that CHR individuals tend to experience stressful life events (LE) and daily hassles (DH) as more subjectively stressful than healthy individuals. The present study utilizes data from the North American Prodrome Longitudinal Study Phase 2 (NAPLS-2) to test the hypotheses that (1) CHR individuals manifest higher self-reported stress in response to both LE and DH when compared to healthy controls (HC), (2) group differences in self-reported stress increase with age, (3) baseline self-reported stress is associated with follow-up clinical status, and (4) there is a sensitization effect of LE on the response to DH. In contrast to some previous research, the present findings indicate that the CHR group (N=314) reported exposure to more LE when compared to the HC group (N=162). As predicted, CHR participants rated events as more stressful, and those who progressed to psychosis reported a greater frequency of LE and greater stress from events compared to those whose prodromal symptoms remitted. There was also some evidence of stress-sensitization; those who experienced more stress from LE rated current DH as more stressful. The results indicate that the "prodromal" phase is a period of heightened stress and stress sensitivity, and elevated cumulative lifetime exposure to stressful events may increase reactions to current stressors.

Clinicians and researchers in Canada and the United States have established a number of early intervention programs and research sites on the early course of psychosis and the prodromal period that commonly precedes psychotic disorders. In Canada, early detection and treatment programs for psychosis have been established in many areas of the country, and typically serve specific catchment areas. Canadian research on early psychosis is often built on to these clinical sites, and covers a broad array of topics including interventions during the prodromal stage of the illness, treatment-seeking behaviors, and development of optimal pharmacological and psychosocial treatment approaches for early psychosis. In the United States, clinical programs for early intervention in psychosis are often located at academic programs with ongoing research on the early course of psychotic disorders. Researchers from sites across the United States offer a plethora of information, including neuroimaging studies, research on treatment response, and the development of standardized rating scales and research instruments. Researchers from sites in both countries have formed a consortium to launch the North American Prodrome Longitudinal Study, a multi-site collaboration to gain a better understanding of the prodromal period of the illness and prediction of conversion from the prodrome to psychosis.

It is now well established that the utilization of standardized clinical criteria can enhance prediction of psychosis. These criteria are primarily concerned with the presence and severity of attenuated positive symptoms. Because these symptom criteria are used to derive algorithms for designating clinical high risk (CHR) status and for maximizing prediction of psychosis risk, it is important to know whether the symptom ratings vary as a function of demographic factors that have previously been linked with symptoms in diagnosed psychotic patients. Using a sample of 356 CHR individuals from the NAPLS-II multi-site study, we examined the relation of three sex, age, and educational level, with the severity of attenuated positive symptom scores from the Scale of Prodromal Symptoms (SOPS). Demographic factors accounted for little of the variance in symptom ratings (5-6%). Older CHR individuals manifested more severe suspiciousness, and female CHR participants reported more unusual perceptual experiences than male participants. Contrary to prediction, higher educational level was associated with more severe ratings of unusual thought content, but less severe perceptual abnormalities. Overall, sex, age and education were modestly related to unusual thought content and perceptual abnormalities, only, suggesting minimal implication for designating CHR status and predicting psychosis-risk.

Background Heightened Stress has been shown to have acute adverse effects on cognitive function, and both stress and cognitive deficits have been found to be inversely associated with hippocampal volume reduction in both healthy and clinical samples. Further, heightened stress and cognitive deficits have been observed in individuals at clinical high risk (CHR) for psychosis in the North American Prodrome Longitudinal Study (NAPLS-2) as well as other studies of CHR groups. The present study utilizes data from NAPLS-2 to examine the relation of acute stress and hippocampal volume with cognitive performance in healthy youth and those at CHR for psychosis. Both the independent and additive relations of daily stress and hippocampal volume (HV) on cognition are examined. Methods The sample was 666 participants (CHR=476; HC=190) who completed MRI scans, as well as measures of stress and cognitive function at the NAPLS-2 baseline assessment. The self-report stress measure was the Daily Stress Inventory (DSI) and cognitive performance was assessed with tests from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery (the Brief Assessment of Cognition in Schizophrenia [BACS]: Symbol Coding, Category Fluency: Animal Naming Trail Making Test: Part A [TMT], Continuous Performance Test—Identical Pairs [CPT-IP], Hopkins Verbal Learning Test—Revised [HVLT-R], Brief Visuospatial Memory Test—Revised [BVMT-R], Neuropsychological Assessment Battery® (NAB): Mazes, and Wechsler memory Scale [WMS]). Hierarchical Linear regression analyses were conducted controlling for subject age, sex and intracranial volume (ICV) with test scores as the dependent measures and DSI scores and hippocampal volume as the predictors. Results As expected, across subject groups, age was positively associated with performance on all of the cognitive measures, and females scored higher than males on the CPT-IP, WMS, and TMT. ICV was positively linked with performance on the TMT, WMS, NAB Mazes, CPT-IP, and BACS. For HC and CHR subjects combined, after entering covariates (sex, age and ICV), DSI, but not HV, was inversely associated with performance on the BVMT, HVLT, CPT-IP, and WMS. Neither DSI nor HV predicted performance on the NAB mazes or the BACS, beyond the variance accounted for by covariates. When analyses were conducted separately for the HC and CHR groups, DSI was not predictive of performance. Discussion The present findings indicate that self-reported daily stress is inversely associated with cognitive performance on a variety of measures, and that this relation is not mediated by HV or any of the covariates in the combined sample of HC and CHR youth. Because the two groups differ in DSI scores, with CHR youth showing significantly higher stress scores, the combined samples represent a broader range of scores than either group alone. Thus, the within-group range of DSI scores is constrained and DSI is not predictive of performance within group. Instead, it appears that elevated stress is one factor contributing to cognitive deficits in CHR youth.

Background A dysregulated immune system is implicated in the development of psychotic disorders. Persons with schizophrenia have altered levels of circulating immune cell signaling molecules (cytokines), and elevation of specific cytokines predict conversion to psychosis in persons at clinical high risk. Whether these peripheral signals are a causal or a secondary phenomenon is unclear. But, subpopulations of circulating immune cells do regulate the brain from meningeal and perivascular locations influencing cognition, mood, and behavior, and thus may be relevant to schizophrenia vulnerability. Hematopoietic stem cells in the bone marrow differentiate into cascading subtypes depending on signals from other organs, especially the brain. For example, a monocyte subpopulation emerges with repeated social defeat that establish the persistence of anxiety-like behaviors; blocking their release or inhibiting their attachment to brain vascular endothelium prevents the emergence of anxiety-like behaviors. In humans, a similar monocyte subpopulation is associated with social isolation and other adversities including low SES, chronic stress, and bereavement. Methods The North American Prodrome Longitudinal Study (NAPLS2) is an eight-site observational study of predictors and mechanisms of conversion to psychosis The full cohort includes 763 at clinical high risk (CHR) based on the Criteria of Prodromal State (COPS) and 279 demographically similar unaffected comparison (UC) subjects. Methylation of whole blood DNA collected in PAXgene tubes at baseline was analyzed with the Illumina 450k array in a subgroup of 59 subjects who converted to psychosis (CHR-C), 84 CHR subjects followed for 2 years who did not develop psychosis (CHR-NC) and 67 unaffected subjects (UC). Our analyses focused on methylation of promoter regions of genes, associated with gene expression. Classifier construction used Coarse Approximation Linear Function (CALF) with bootstrapping of 1000 random 80% subsets with replacement to determine statistical likelihood. Results We found highly overlapping sets of differentially methylated promoter regions in CHR-C subjects compared to CHR-NC and to UC subjects. A set of 10 markers correctly classified CHR-C and CHR-NC subjects with high accuracy (AUC=0.94, 95% CI 0.89–0.98). Included was SIRT1, a gene that is upregulated with HSV reactivation. Discussion Circulating immune cells excerpt powerful influences on mood, cognition and behavior. An obvious example is the experience of most human with “sickness syndrome”, characterized by apathy, avolition, and withdrawal, and triggered by immune-cell-released cytokines producing an adaptive, resource conserving, behavioral response. While at an early stage, our findings further implicate immune system dysregulation as a mechanism in the development of psychosis.

Background Heightened Stress has been shown to have acute adverse effects on cognitive function, and both stress and cognitive deficits have been found to be inversely associated with hippocampal volume reduction in both healthy and clinical samples. Further, heightened stress and cognitive deficits have been observed in individuals at clinical high risk (CHR) for psychosis in the North American Prodrome Longitudinal Study (NAPLS-2) as well as other studies of CHR groups. The present study utilizes data from NAPLS-2 to examine the relation of acute stress and hippocampal volume with cognitive performance in healthy youth and those at CHR for psychosis. Both the independent and additive relations of daily stress and hippocampal volume (HV) on cognition are examined. Methods The sample was 666 participants (CHR=476; HC=190) who completed MRI scans, as well as measures of stress and cognitive function at the NAPLS-2 baseline assessment. The self-report stress measure was the Daily Stress Inventory (DSI) and cognitive performance was assessed with tests from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery (the Brief Assessment of Cognition in Schizophrenia [BACS]: Symbol Coding, Category Fluency: Animal Naming Trail Making Test: Part A [TMT], Continuous Performance Test—Identical Pairs [CPT-IP], Hopkins Verbal Learning Test—Revised [HVLT-R], Brief Visuospatial Memory Test—Revised [BVMT-R], Neuropsychological Assessment Battery® (NAB): Mazes, and Wechsler memory Scale [WMS]). Hierarchical Linear regression analyses were conducted controlling for subject age, sex and intracranial volume (ICV) with test scores as the dependent measures and DSI scores and hippocampal volume as the predictors. Results As expected, across subject groups, age was positively associated with performance on all of the cognitive measures, and females scored higher than males on the CPT-IP, WMS, and TMT. ICV was positively linked with performance on the TMT, WMS, NAB Mazes, CPT-IP, and BACS. For HC and CHR subjects combined, after entering covariates (sex, age and ICV), DSI, but not HV, was inversely associated with performance on the BVMT, HVLT, CPT-IP, and WMS. Neither DSI nor HV predicted performance on the NAB mazes or the BACS, beyond the variance accounted for by covariates. When analyses were conducted separately for the HC and CHR groups, DSI was not predictive of performance. Discussion The present findings indicate that self-reported daily stress is inversely associated with cognitive performance on a variety of measures, and that this relation is not mediated by HV or any of the covariates in the combined sample of HC and CHR youth. Because the two groups differ in DSI scores, with CHR youth showing significantly higher stress scores, the combined samples represent a broader range of scores than either group alone. Thus, the within-group range of DSI scores is constrained and DSI is not predictive of performance within group. Instead, it appears that elevated stress is one factor contributing to cognitive deficits in CHR youth.

Background In the clinical high risk (CHR) for psychosis literature, typically, the focus is on determining the risk of conversion to psychosis. However, between 70% and 85% of youth who meet CHR criteria do not develop psychosis during the follow-up period of the study in which they participate. The aim of this study is to focus on CHR youth who did not transition to psychosis and to determine whether there are differences amongst them. Methods The North American Prodrome Longitudinal Study (NAPLS-2) is an 8-site prospective, longitudinal study including 764 help-seeking youth, age 12–35, meeting criteria for a psychosis risk syndrome based on the Structured Interview for Psychosis-risk Syndromes (SIPS), and 279 healthy controls (HC). For this analysis, only youth who did not make a transition to psychosis and completed 2 years of follow-up (n=278, 154 males, 124 females; mean age 18.8) were included. At the 24-month final assessment, the sample was divided into 3 groups: 1) those in remission, determined by scores ≤2 on all 5 attenuated psychotic symptoms on The Scale of Psychosis-risk Symptoms (SOPS); 2) symptomatic, determined by still having a rating of 3–5 on any one of the 5 attenuated psychotic symptoms on the SOPS; 3) prodromal progression, determined by continuing to meet the Criteria of Psychosis-risk Syndromes (COPS). The groups were compared at baseline and at 24-month follow-up on: age, gender, the presence of a current and lifetime psychiatric diagnosis, and social and role functioning. The use of antipsychotic medication was examined across all assessments (baseline, 6-, 12-, 18- & 24 months) using Generalized Linear Models to examine differences among the 3 groups. Results Among the participants, 110 (39.57%) were in-remission, 93 (33.45%) symptomatic, and 75 (26.98%) prodromal progression. At baseline there were no significant differences in age, gender, social and role functioning, or SCID diagnoses except on current PTSD (p=.001) with most cases in the prodromal progression group, and on current anxiety disorder (p=≤.0001) with most cases in the symptomatic group. The prodromal progression had significantly higher ratings on unusual thought content compared to the in-remission group and significantly higher ratings on suspiciousness than the symptomatic group. At 24-month follow-up there were significant differences in negative symptoms (p=≤.0001) between prodromal progression (M=9.19), symptomatic (M=8.84), and in remission (M=5.99) groups; and social functioning (p=≤.005; M=6.56, M=6.68, M=7.20 respectively). Although the in-remission group had the highest ratings on social functioning these were significantly lower in social (M=7.20) and role (M=6.68) functioning than HC (M=8.73, M=8.62 respectively). The groups did not differ on their use of antipsychotics over the course of their 2 years in the study. Discussion There were very few differences on baseline measures amongst the different two-year outcome groups. At 2 years, even though those in remission had improved social and role functioning relative to the other 2 groups, they still had lower social and role functioning than HC.