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

Abstract

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, p_FDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, p_spin = 0.024), but not BD (r = 0.166, p_spin = 0.205) or MDD (r = -0.274, p_spin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, p_spin = 0.006), BD (rho = -0.672, p_spin = 0.009), and MDD (rho = -0.692, p_spin = 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.

Fig. 1. Effect sizes of partial correlation (r) between cortical thickness, surface area and schizotypy.

A Cortical thickness, (B) Surface area. Effect sizes for all regions depicted were corrected for age, sex and global cortical thickness or total surface area, respectively. Red rectangle highlights effects surviving false discovery rate (FDR) correction (p_FDR < 0.05).

Fig. 2. Cortical maps of regional effect sizes for associations with schizotypy.

A Cortical thickness, (B) Surface area. C Forest plot of the significant association between mOFC/vmPFC thickness and schizotypy, after false discovery rate (FDR) correction (p_FDR < 0.05).

Fig. 3. Effect sizes of partial correlation (r) between subcortical volumes and schizotypy.

Effect sizes for all subcortical volumes depicted were corrected for age, sex and intracranial volume (ICV).

Fig. 4. Pattern similarity between cortical thickness effects in schizotypy and major psychiatric disorders.

Abbreviations of the cortical regions are adopted from the brainGraph package and shown for regions with the most positive and negative effect sizes (r): FUS fusiform gyrus, ITG inferior temporal gyrus, iCC isthmus cingulate cortex, MOF medial orbitofrontal cortex, paraC paracentral lobule, pOPER pars opercularis of inferior frontal gyrus, periCAL pericalcarine cortex, rACC rostral anterior cingulate cortex, FP frontal pole, INS insula. L left, R right.

Fig. 5. Pattern similarity between subcortical volume effects in schizotypy and major psychiatric disorders.

Abbreviations of subcortical regions are adopted from the brainGraph package and are shown for regions with the most positive and negative effect sizes (r): HIPP hippocampus, PALL pallidum, PUT putamen, LVEN lateral ventricle, l left, r right.