Improving prediction of psychosis in youth at clinical high-risk: pre-baseline symptom duration and cortical thinning as moderators of the NAPLS2 risk calculator.

BACKGROUND: Clinical implementation of risk calculator models in the clinical high-risk for psychosis (CHR-P) population has been hindered by heterogeneous risk distributions across study cohorts which could be attributed to pre-ascertainment illness progression. To examine this, we tested whether the duration of attenuated psychotic symptom (APS) worsening prior to baseline moderated performance of the North American prodrome longitudinal study 2 (NAPLS2) risk calculator. We also examined whether rates of cortical thinning, another marker of illness progression, bolstered clinical prediction models. METHODS: Participants from both the NAPLS2 and NAPLS3 samples were classified as either 'long' or 'short' symptom duration based on time since APS increase prior to baseline. The NAPLS2 risk calculator model was applied to each of these groups. In a subset of NAPLS3 participants who completed follow-up magnetic resonance imaging scans, change in cortical thickness was combined with the individual risk score to predict conversion to psychosis. RESULTS: The risk calculator models achieved similar performance across the combined NAPLS2/NAPLS3 sample [area under the curve (AUC) = 0.69], the long duration group (AUC = 0.71), and the short duration group (AUC = 0.71). The shorter duration group was younger and had higher baseline APS than the longer duration group. The addition of cortical thinning improved the prediction of conversion significantly for the short duration group (AUC = 0.84), with a moderate improvement in prediction for the longer duration group (AUC = 0.78). CONCLUSIONS: These results suggest that early illness progression differs among CHR-P patients, is detectable with both clinical and neuroimaging measures, and could play an essential role in the prediction of clinical outcomes.

Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Life Event Stress and Reduced Cortical Thickness in Youth at Clinical High Risk for Psychosis and Healthy Control Subjects.

BACKGROUND: A decline in cortical thickness during early life appears to be a normal neuromaturational process. Accelerated cortical thinning has been linked with conversion to psychosis among individuals at clinical high risk for psychosis (CHR-P). Previous research indicates that exposure to life event stress (LES) is associated with exaggerated cortical thinning in both healthy and clinical populations, and LES is also linked with conversion to psychosis in CHR-P. To date, there are no reports on the relationship of LES with cortical thickness in CHR-P. This study examines this relationship and whether LES is linked with cortical thinning to a greater degree in individuals at CHR-P who convert to psychosis compared with individuals at CHR-P who do not convert and healthy control subjects. METHODS: Controlling for age and gender (364 male, 262 female), this study examined associations between LES and baseline cortical thickness in 436 individuals at CHR-P (375 nonconverters and 61 converters) and 190 comparison subjects in the North American Prodrome Longitudinal Study. RESULTS: Findings indicate that prebaseline cumulative LES is associated with reduced baseline cortical thickness in several regions among the CHR-P and control groups. Evidence suggests that LES is a risk factor for thinner cortex to the same extent across diagnostic groups, while CHR-P status is linked with thinner cortex in select regions after accounting for LES. CONCLUSIONS: This research provides additional evidence to support the role of LES in cortical thinning in both healthy youth and those at CHR-P. Potential underlying mechanisms of the findings and implications for future research are discussed.

Discriminatory experiences predict neuroanatomical changes and anxiety among healthy individuals and those at clinical high risk for psychosis.

Individuals face discrimination based on characteristics including race/ethnicity, gender, age, and disability. Discriminatory experiences (DE) are associated with poor psychological health in the general population and with worse outcomes among individuals at clinical high risk for psychosis (CHR). Though the brain is sensitive to stress, and brain structural change is a well-documented precursor to psychosis, potential relationships between DE and brain structure among CHR or healthy individuals are not known. This report assessed whether lifetime DE are associated with cortical thinning and clinical outcomes across time, after controlling for discrimination-related demographic factors among CHR individuals who ultimately do (N = 57) and do not convert to psychosis (N = 451), and healthy comparison (N = 208) participants in the North American Prodrome Longitudinal Study 2. Results indicate that DE are associated with thinner cortex across time in several cortical areas. Thickness in several right hemisphere regions partially mediates associations between DE and subsequent anxiety symptoms, but not attenuated positive symptoms of psychosis. This report provides the first evidence to date of an association between DE and brain structure in both CHR and healthy comparison individuals. Results also suggest that thinner cortex across time in areas linked with DE may partially explain associations between DE and cross-diagnostic indicators of psychological distress.

Convergent molecular, cellular, and cortical neuroimaging signatures of major depressive disorder.

Major depressive disorder emerges from the complex interactions of biological systems that span genes and molecules through cells, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to depression requires a multiscale approach, encompassing measures of brain structure and function as well as genetic and cell-specific transcriptional data. Here, we examine anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Brain Genomics Superstruct Project, and Enhancing NeuroImaging through Meta Analysis (ENIGMA; combined n ≥ 23,723). Integrative analyses incorporate measures of cortical gene expression, postmortem patient transcriptional data, depression genome-wide association study (GWAS), and single-cell gene transcription. Neuroimaging correlates of depression and negative affect were consistent across three independent datasets. Linking ex vivo gene down-regulation with in vivo neuroimaging, we find that transcriptional correlates of depression imaging phenotypes track gene down-regulation in postmortem cortical samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data reveal somatostatin interneurons and astrocytes to be consistent cell associates of depression, through both in vivo imaging and ex vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS-derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multiscale approaches, the transcriptional correlates of depression-linked brain function and structure were enriched for disorder-relevant molecular pathways. These findings bridge levels to connect specific genes, cell classes, and biological pathways to in vivo imaging correlates of depression.

Transcriptional and imaging-genetic association of cortical interneurons, brain function, and schizophrenia risk.

Inhibitory interneurons orchestrate information flow across the cortex and are implicated in psychiatric illness. Although interneuron classes have unique functional properties and spatial distributions, the influence of interneuron subtypes on brain function, cortical specialization, and illness risk remains elusive. Here, we demonstrate stereotyped negative correlation of somatostatin and parvalbumin transcripts within human and non-human primates. Cortical distributions of somatostatin and parvalbumin cell gene markers are strongly coupled to regional differences in functional MRI variability. In the general population (n = 9,713), parvalbumin-linked genes account for an enriched proportion of heritable variance in in-vivo functional MRI signal amplitude. Single-marker and polygenic cell deconvolution establish that this relationship is spatially dependent, following the topography of parvalbumin expression in post-mortem brain tissue. Finally, schizophrenia genetic risk is enriched among interneuron-linked genes and predicts cortical signal amplitude in parvalbumin-biased regions. These data indicate that the molecular-genetic basis of brain function is shaped by interneuron-related transcripts and may capture individual differences in schizophrenia risk.