Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype

Schizophrenia polygenic risk during typical development reflects multiscale cortical organization

Schizophrenia is widely recognized as a neurodevelopmental disorder, but determining neurodevelopmental features of schizophrenia requires a departure from classic case-control designs. Polygenic risk scoring for schizophrenia (PRS-SCZ) enables investigation of the influence of genetic risk for schizophrenia on cortical anatomy during neurodevelopment and prior to disease onset. PRS-SCZ and cortical morphometry were assessed in typically developing children (3 – 21 years) using T1-weighted MRI and whole genome genotyping (n=390) from the Pediatric Imaging, Neurocognition and Genetics (PING) cohort. Then, we sought to contextualise the findings using (i) age-matched transcriptomics, (ii) gradients of cortical differentiation and (iii) case-control differences of major psychiatric disorders. Higher PRS-SCZ was associated with greater cortical thickness in typically developing children, while surface area and cortical volume showed only subtle associations. Greater cortical thickness was most prominent in areas with heightened gene expression for dendrites and synapses. The pattern of PRS-SCZ associations with cortical thickness reflected functional specialisation in the cortex and was spatially related to cortical abnormalities of patient populations of schizophrenia, bipolar disorder, and major depression. Finally, age interaction models indicated PRS-SCZ effects on cortical thickness were most pronounced between ages 3 and 6, suggesting an influence of PRS-SCZ on cortical maturation early in life. Integrating imaging-genetics with multi-scale mapping of cortical organization, our work contributes to an emerging understanding of how risk for schizophrenia and related disorders manifest in early life

Schizophrenia polygenic risk during typical development reflects multiscale cortical organization

Schizophrenia is widely recognized as a neurodevelopmental disorder, but determining neurodevelopmental features of schizophrenia requires a departure from classic case-control designs. Polygenic risk scoring for schizophrenia (PRS-SCZ) enables investigation of the influence of genetic risk for schizophrenia on cortical anatomy during neurodevelopment and prior to disease onset. PRS-SCZ and cortical morphometry were assessed in typically developing children (3 – 21 years) using T1-weighted MRI and whole genome genotyping (n=390) from the Pediatric Imaging, Neurocognition and Genetics (PING) cohort. Then, we sought to contextualise the findings using (i) age-matched transcriptomics, (ii) gradients of cortical differentiation and (iii) case-control differences of major psychiatric disorders. Higher PRS-SCZ was associated with greater cortical thickness in typically developing children, while surface area and cortical volume showed only subtle associations. Greater cortical thickness was most prominent in areas with heightened gene expression for dendrites and synapses. The pattern of PRS-SCZ associations with cortical thickness reflected functional specialisation in the cortex and was spatially related to cortical abnormalities of patient populations of schizophrenia, bipolar disorder, and major depression. Finally, age interaction models indicated PRS-SCZ effects on cortical thickness were most pronounced between ages 3 and 6, suggesting an influence of PRS-SCZ on cortical maturation early in life. Integrating imaging-genetics with multi-scale mapping of cortical organization, our work contributes to an emerging understanding of how risk for schizophrenia and related disorders manifest in early life

Latent clinical-anatomical dimensions of schizophrenia

Widespread structural brain abnormalities have been consistently reported in schizophrenia, but their relation to the heterogeneous clinical manifestations remains unknown. In particular, it is unclear whether anatomical abnormalities in discrete regions give rise to discrete symptoms or whether distributed abnormalities give rise to the broad clinical profile associated with schizophrenia. Here, we apply a multivariate data-driven approach to investigate covariance patterns between multiple-symptom domains and distributed brain abnormalities in schizophrenia. Structural magnetic resonance imaging and clinical data were derived from one discovery sample (133 patients and 113 controls) and one independent validation sample (108 patients and 69 controls). Disease-related voxel-wise brain abnormalities were estimated using deformation-based morphometry. Partial least-squares analysis was used to comprehensively map clinical, neuropsychological, and demographic data onto distributed deformation in a single multivariate model. The analysis identified 3 latent clinical-anatomical dimensions that collectively accounted for 55% of the covariance between clinical data and brain deformation. The first latent clinical-anatomical dimension was replicated in an independent sample, encompassing cognitive impairments, negative symptom severity, and brain abnormalities within the default mode and visual networks. This cognitive-negative dimension was associated with low socioeconomic status and was represented across multiple races. Altogether, we identified a continuous cognitive-negative dimension of schizophrenia, centered on 2 intrinsic networks. By simultaneously taking into account both clinical manifestations and neuroanatomical abnormalities, the present results open new avenues for multi-omic stratification and biotyping of individuals with schizophrenia

Orbitofrontal-Striatal Structural Alterations Linked to Negative Symptoms at Different Stages of the Schizophrenia Spectrum

Negative symptoms such as anhedonia and apathy are among the most debilitating manifestations of schizophrenia (SZ). Imaging studies have linked these symptoms to morphometric abnormalities in 2 brain regions implicated in reward and motivation: the orbitofrontal cortex (OFC) and striatum. Higher negative symptoms are generally associated with reduced OFC thickness, while higher apathy specifically maps to reduced striatal volume. However, it remains unclear whether these tissue losses are a consequence of chronic illness and its treatment or an underlying phenotypic trait. Here, we use multicentre magnetic resonance imaging data to investigate orbitofrontal-striatal abnormalities across the SZ spectrum from healthy populations with high schizotypy to unmedicated and medicated first-episode psychosis (FEP), and patients with chronic SZ. Putamen, caudate, accumbens volume, and OFC thickness were estimated from T1-weighted images acquired in all 3 diagnostic groups and controls from 4 sites (n = 337). Results were first established in 1 discovery dataset and replicated in 3 independent samples. There was a negative correlation between apathy and putamen/accumbens volume only in healthy individuals with schizotypy; however, medicated patients exhibited larger putamen volume, which appears to be a consequence of antipsychotic medications. The negative association between reduced OFC thickness and total negative symptoms also appeared to vary along the SZ spectrum, being significant only in FEP patients. In schizotypy, there was increased OFC thickness relative to controls. Our findings suggest that negative symptoms are associated with a temporal continuum of orbitofrontal-striatal abnormalities that may predate the occurrence of SZ. Thicker OFC in schizotypy may represent either compensatory or pathological mechanisms prior to the disease onset

Cortical and subcortical neuroanatomical signatures of schizotypy in 3004 individuals assessed in a worldwide ENIGMA study

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12–68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = −0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = −0.690, pspin = 0.006), BD (rho = −0.672, pspin = 0.009), and MDD (rho = −0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype