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 , 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,indoor plant grow racks 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 multi-modal 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.Gray and white matter morphology have been investigated in detail in the PNC. 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 microstructure, 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 sub-threshold 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,indoor plant growing rack 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 . Utilizing data from the IMAGEN study that included longitudinal fMRI and measures of PS at follow-up, Papanstasiou et al. observed increases in right frontal activation during reward anticipation and feedback of win from age 14 to 19 that was associated with PS at age 19; this increase over time was not observed in youth who did not report PS. The authors speculate whether this finding could be a possible compensatory mechanism. However, given that PS were not assessed at age 14, results are to be interpreted with caution. Resting-state fMRI has become a popular tool to study how distant brain areas are functionally connected. Unlike task-based fMRI, it is less susceptible to performance and vigilance differences between groups, which facilitates interpretation of group differences. Again, the PNC has allowed large-scale investigation of functional connectivity across development. With regard to static functional connectivity , Satterthwaite et al. showed that PS youth exhibited similar patterns of dysconnectivity to patients with overt psychosis. In particular, they observed hyper connectivity within the default-mode network and reduced functional connectivity within the executive control network . However, in one of the largest pediatric population-based samples Karcher et al. recently reported hypoconnectivity within the DMN and within the executive control networks that is associated with increased PS in 9- to 11-year old children . These differences in observed hypo- vs.Nevertheless, there has been a similar dissonance in adult cohorts with overt psychosis, where both hypo- and hyper connectivity of the DMN and executive control networks has been described .
In an elegant follow-up study that applied multivariate sparse canonical correlation analysis to the PNC resting state data, Xia and colleagues corroborated that in fact the segregation between the DMN and executive control networks is a common feature across multiple psychopathology dimensions, but the psychosis dimension shows the strongest effect . Moreover, a recent study of this cohort that investigated dynamic properties of functional connectivity, i.e., time-varying patterns of whole-brain connectivity, found that previously described dysconnectivity between the DMN and executive control networks in youth experiencing PS is time-dependent, and only occurs during certain periods of a resting-state scan, whereas dysconnectivity in visual and sensorimotor areas is much more pervasive . The Human Connectome Project is an adult cohort in which resting-state fMRI as well as self-reported PS were acquired. Here, PS were significantly inversely correlated with cognitive abilities, an effect that was partially mediated by global efficiency of the executive control network, a measure of network integration . With regard to dynamic functional connectivity in the HCP, it has recently been shown that adults experiencing PS spend more time in a dynamic state, i.e., a distinct time-varying connectivity pattern, characterized by reduced connectivity within the DMN ; a finding that mirrors previous results in studies on individuals with overt psychosis .Even though pediatric population neuroscience is still in its infancy, studies overwhelmingly find that PS in childhood and adolescence pose a risk factor for later development of overt psychiatric illness, and are overall associated with reduced functioning and quality of life. Many early intervention specialty programs offer a coherent multi-modal treatment framework for clients, including psychopharmacological treatment, psychotherapy and psychoeducation as well as vocational counseling. Meta-analytic results suggest that multidisciplinary therapies can delay or prevent transition to overt psychosis . Low risk psychosocial interventions targeting functioning have been shown to be effective in CHR youth; such approaches are likely to be also effective in a broader audience . These results find consideration in the recently published guidelines of the European Psychiatric Association where a dual treatment consisting of cognitive behavioral therapy and pharmacological treatment yields recommendation grade A for adult CHR individuals. For children and adolescents experiencing PS, as targeted by pediatric population neuroscience, the expert recommendation is specific psychological interventions to improve functioning and close monitoring of PS. PS are often preceded by non-specific behavioral and emotional problems in childhood related to increased adversity and trauma. Since these precursors in themselves pose a risk for development of diverse psychopathologies, we argue – as others before us – that these childhood-onset problems offer another promising target for population-based preventive interventions. However, causal mechanisms from abnormal neurodevelopment to subsequent psychopathology are not yet understood and require further longitudinal research. Since only a minority of individuals with PS access appropriate mental health services, it will be important to implement services appropriate to a broad audience, for example in schools. It will be essential to identify those individuals at highest risk, and to reduce the number of false positives in order to provide cost effective services and to reduce stigma. Individual risk calculators developed and tested in CHR cohorts may not work as well when broadening the target audience. With sufficient longitudinal data, questionnaires such as the Psychosis Questionnaire, Brief Version may be amenable for community samples, and may be used to develop risk calculators for youth in the general population. Given the evidence presented here and results from the Outreach and Support in South London and Headspace initiatives , we argue that findings from population-based studies are adequate for guiding policy-making toward further emphasis on public health efforts, although more systematic research is needed in this area. Destigmatization initiatives for mental illness have been shown to be effective in reducing discrimination and stigma , and broadly accessible mental health programs like Headspace and Jigsaw are promising to make a difference in the field of adolescent mental health . However, the specific efficacy of these programs warrants further study, and caution is advised to not over-pathologize potentially transient occurrence of mental health problems.The prevalence of alcohol, tobacco, and other substance use is higher among gay, bisexual, and other men who have sex with men than in the overall population . Although Hughes and Eliason noted that substance and alcohol use have declined in lesbian, gay, bisexual, and transgender populations, the prevalence of heavy alcohol and substance use remains high among younger lesbians and gay men, and in some cases older lesbians and gay men.