A recent follow-up of this cohort reported that PS at age 11 were associated not only with a diagnosis of schizophrenia at age 38 7.24) but also with diagnoses of Post Traumatic Stress Disorder , substance dependence , depression , and anxiety . Higher rates of PS at age 11 further predicted suicide/ suicide attempts at age 38, even when controlling for other psychiatric disorders at age 11 [the 15-year follow-up study of the Dunedin cohort at age 26 reported very similar findings ]. It is important to note, however, that PS were assessed with the Diagnostic Interview Schedule for Children, an instrument that includes only 5 questions on positive PS. The Avon Longitudinal Study of Parents and Children , with over 13,000 study participants, includes a total of 68 assessment points between birth and age 18. Niarchou et al. reported that, similar to results from the Dunedin cohort, PS at age 12 were predictive of a psychotic disorder at age 18 12.7. Interestingly, nonspecific symptoms such as depersonalization and sub-psychotic unusual experiences were predictive of a psychotic disorder and depression at age 18 . Even though, ALSPaC also assessed only positive PS, the semi-structured PLIKSi instrument covers the three major domains of positive PS, i.e., hallucinations, delusions, and bizarre thinking, and therefore reflects a broader spectrum of PS . Overall, in the general population it appears that PS during childhood and adolescence increase the risk of later development of a broad range of psychiatric illnesses . PS in help-seeking individuals fulfilling CHR criteria may be more specific in terms of predicting psychosis onset even though rates of co-occurring nonpsychotic disorders are also higher in these cohorts relative to the general population . Although their etiology is not well understood,grow tray PS throughout life are often preceded and accompanied by emotional and behavioral problems, which in turn are often associated with life adversities.

Findings from the ALSPaC sample further confirmed previously described risk factors. In particular, early neurodevelopmental problems such as autism spectrum symptoms, asphyxia during birth, lower IQ, and delayed early motor development were specifically associated with PS in adolescence . Bolhuis et al. highlighted emotional and behavioral problems at age 3 and 6 as the earliest significant predictors of PS at age 10. These encompassed depressive symptoms, aggressive behavior, anxiety, sleep difficulties, attention problems, and somatic complaints. Interestingly, emotional and behavioral problems also partially explained the association between previously described risk factors such as autistic traits and childhood adversities and PS, rendering it likely that emotional problems are a core risk factor or precursor for later PS. Further, the authors hypothesize that PS can manifest differently across the lifespan, ranging from emotional problems in early childhood to sub-clinical PS in late childhood and adolescence, and severe mental illness in adulthood. However, difficulties in validly assessing PS in younger children could lead to a distortion of the true association between childhood emotional problems and PS . A twin study further supports an association between childhood emotional and behavioral problems and adolescent PS by showing a modest genetic overlap across these phenotypes . Further, lack of certain personal resources such as low optimism, low self-esteem, and high avoidance, in addition to emotional problems, have been reported as significant predictors of PS during adolescence . Early life stress and childhood adversities are associated with emotional and behavioral problems not only in childhood and adolescence but across the lifespan . In the largest population-based study to date, the World Health Organization Mental Health Survey , McGrath and colleagues confirmed that childhood adversities are associated with an at least two-fold increased risk for developing PS, in a dose-response relationship . Childhood adversities characterizing ‘maladaptive family functioning’ posed a somewhat stronger association with later onset of PS than ‘other childhood adversities’ .

Interestingly, when adjusting for other mental illnesses with onset prior to PS, the association between childhood adversities and PS onset during adolescence became non-significant. This finding suggests that childhood adversities are not only a risk factor for adolescent-onset PS, but also other psychopathological symptoms with onset prior to adolescence, which in turn may lead to PS. Finally, an often-discussed risk factor for the consecutive development of PS is cannabis use; longitudinal results from the Netherlands Mental Health and Incidence Study reported that baseline cannabis use predicted PS at follow-up . Recent publications conclude that the evidence for this association is sufficient for policy makers to take this risk into consideration when further discussing legalizing cannabis . Recently, genetic studies have made great progress in elucidating the genetic architecture of severe mental illnesses. In the majority of cases, risk for severe mental illnesses appears to be attributable to the cumulative impact of multiple genes, where each gene individually explains only a small amount of variance, but the sum of risk alleles across all identified variants accounts for up to 18% of variance in schizophrenia diagnosis . As such, investigation of poly genic risk scores , based on effect sizes of common variants associated with schizophrenia and other disorders has become increasingly common in population-based studies. Studies applying PRS to developmental cohorts have recently emerged. For example, in the ALSPaC cohort schizophrenia PRS was significantly associated with negative symptoms and anxiety during adolescence, but not with positive symptoms, again suggesting that the genetic basis of PS may present differently across development . In line with behavioral studies, Riglin et al. highlighted associations between schizophrenia PRS and diverse problems of childhood development at ages 7 to 9, such as lower IQ and poor social and language skills . A recent study combined three major population-based cohorts [ALSPaC, TEDS , and CATSS ], identifying significant associations between schizophrenia PRS and different symptom domains: hallucinations and paranoia , anhedonia, cognitive disorganization, and parent-rated negative symptoms . Interestingly, bipolar disorder PRS was also significantly associated with hallucinations and paranoia, even when including individuals who scored zero on this scale.

PRS for major depression was further associated with anhedonia and parent-reported negative symptoms. In a follow-up study taking a multivariate factor analytic approach, Jones et al. found schizophrenia PRS was significantly associated with multiple psychopathology factors . However, these specific effects vanished when including a general psychopathology factor, suggesting that psychopathology during adolescence may be explained with one broad factor. PS during adolescence are rather non-specific and pose risk for a variety of severe mental illnesses. Loohuis and colleagues therefore utilized a novel multi-trait approach including PRS of a broad range of psychiatric disorders, including neurodevelopmental disorders as well as brain and cognitive traits, to assess the association between these genetic risk factors and PS in youth. Interestingly, the ADHD PRS was the only significant predictor of PS in youth of European-American ancestry in the PNC , even after removing individuals endorsing any ADHD symptoms to avoid confounds related to phenotypic overlap . This finding was replicated in a sample of help-seeking CHR individuals. Further, the association between PS and ADHD PRS was age-dependent, such that the association was strongest in younger children . It is noteworthy that for individuals < 12 years only collateral information on psychopathology was available, which could affect the results. In addition to polygenic risk ,hydroponic trays recent exome sequencing studies have also found that rare and ultra-rare variants contribute to the genetic risk of schizophrenia . Overall, findings from these studies highlight the complex association between genetic risk and PS during adolescence. While such symptoms may be non-specific, and presage later severe mental illnesses, polygenic risk may be indexing global psychopathology as well as risk for specific diagnostic entities. Importantly, because PRS are currently derived from almost entirely European cohorts, their application to non-European ethnic groups is problematic ; collection of ethnically diverse samples is a research imperative. Further, while PRS are far from clinical utility in the general population, as ever-increasing GWAS size improves the strength of these associations, these risk scores may approach clinical utility in enriched populations in the near future. Examples of publicly available population-based datasets in youth that include multimodal imaging and neurocognitive assessments are the PNC and the Adolescent Brain Cognitive Development study. These samples offer unprecedented opportunities for the neuroscience community to study complex brain-behavior interactions during development. In particular, longitudinal data will allow for unique investigations of developmental trajectories. Given the young age of ABCD participants at study baseline it has the potential to capture earliest signs of emotional and behavioral problems associated with subsequent severe mental illnesses. Table 2 summarizes large scale epidemiological cohorts with multi-modal imaging. The PNC has led to a wealth of new findings regarding structural and functional brain alterations in youth experiencing PS; 1,445 youth aged 8 to 21 years were recruited from the greater Philadelphia area and underwent genotyping, multi-modal imaging, and neuropsychological testing. This sample was not ascertained for specific neuropsychiatric problems and includes multi-ethnic youth from various socio-economic backgrounds.

Exclusion criteria were limited, and included significant medical problems, intellectual disability, neurological and/or endocrine conditions, and general MRI contraindications .Importantly, all studies on PS in the PNC applied the same diagnostic criteria, offering comparability across studies . Furthermore, neuroimaging data were acquired with a single MRI scanner, reducing artifacts and heterogeneity due to scanner and study site variability. Reductions in local gray matter volume in youth experiencing PS relative to typically developing youth were observed in bilateral medial temporal lobes, and were also associated with PS severity . Further, a significant age by group interaction suggested that these local reductions in gray matter volume only became apparent in mid-adolescence in youth experiencing PS. This pattern of volume reductions in medial temporal regions mirrors a wealth of such findings not only in individuals with chronic schizophrenia, but also in individuals with first episode psychosis as well as in individuals at clinical high-risk for developing psychosis . Given that the medial temporal lobe in this study included both the amygdala as well as parahippocampal cortex, this finding was followed up with a more detailed parcellation of the temporal lobe: whereas decreased volume of the left amygdala was associated with positive PS, decreased volume of the left entorhinal cortex was correlated with impaired cognition as well as more severe negative and disorganized symptoms , suggesting that variation in these brain structures may contribute to distinct symptom domains. Jalbrzikowski et al. subsequently investigated whole-brain morphology differences in cortical thickness, surface area, and sub-cortical volume in PS youth in this cohort, relative to both youth with bipolar mood symptoms and typically developing youth . This study found thalamic volume reductions that were specific to PS. Again, these findings parallel those observed in individuals with overt psychosis and those at CHR , highlighting the role of the thalamus in neural system disruptions in psychosis. In terms of white matter micro-structure, youth with PS also exhibited reduced fractional anisotropy in the retrolenticular internal capsule and the superior longitudinal fasciculus , possibly reflecting altered axonal diameter and/or myelination . Development of the SLF was associated with cognitive maturation in typically developing youth, an effect that was absent in youth experiencing PS. Overall, alterations of brain morphology observed in these non-clinically ascertained cohorts of youth experiencing subthreshold PS can be interpreted as further evidence for a psychosis continuum, given qualitatively similar alterations observed in individuals with overt illness and those at CHR for psychosis.In terms of functional MRI, task-based brain function and resting state functional connectivity have both been investigated in population-based studies of PS. In the PNC, two MRI paradigms have been acquired: an n-back task probing different working memory loads and an emotion identification task. Working memory is viewed as a function of higher cognitive/ executive functioning consistently shown to be impaired in schizophrenia . Similarly, a wealth of evidence exists for impaired emotional processing in schizophrenia . Wolf et al. found reduced activation in the executive control network in response to increasing working memory demands, concomitant with worse performance, in PS youth relative to typically developing peers . Amygdala activation in response to threatening facial expressions was increased in PS youth compared to unaffected youth and was also positively correlated with positive symptom severity .