Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium

Abstract

Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.

Keywords: Schizophrenia; asymmetry; brain imaging; cortical; subcortical.

Fig. 1.

Average structural asymmetries of the brain in individuals with schizophrenia and unaffected controls. For each bilaterally paired structural measure, the mean asymmetry index (AI) across datasets, weighted by sample size, is shown for individuals with schizophrenia (purple) and unaffected controls (green). A positive AI indicates left > right asymmetry, whereas a negative AI indicates right > left asymmetry. Error bars show pooled SDs. Figure was generated in R using package ggplot2 (69).

Fig. 2.

Map of cortical and subcortical asymmetry differences between individuals with schizophrenia and unaffected controls. Cohen’s d effect sizes from random-effects meta-analysis are projected on inflated left hemisphere cortical surface models (for cortical thickness and surface area) or subcortical structures (for subcortical volumes). Positive effects are shown in red shades (larger leftward or smaller rightward asymmetry in cases versus controls), while negative effects are shown in blue shades (smaller leftward or larger rightward asymmetry in cases versus controls). Gray shades indicate masked out structures. See also Fig. 1 and SI Appendix, Table S4 for directions of effects. Regions significant at p_FDR < 0.05 are labeled and marked with asterisks.