Abnormal asymmetries in subcortical brain volume in schizophrenia

Abstract

Subcortical structures, which include the basal ganglia and parts of the limbic system, have key roles in learning, motor control and emotion, but also contribute to higher-order executive functions. Prior studies have reported volumetric alterations in subcortical regions in schizophrenia. Reported results have sometimes been heterogeneous, and few large-scale investigations have been conducted. Moreover, few large-scale studies have assessed asymmetries of subcortical volumes in schizophrenia. Here, as a work completely independent of a study performed by the ENIGMA consortium, we conducted a large-scale multisite study of subcortical volumetric differences between patients with schizophrenia and controls. We also explored the laterality of subcortical regions to identify characteristic similarities and differences between them. T1-weighted images from 1680 healthy individuals and 884 patients with schizophrenia, obtained with 15 imaging protocols at 11 sites, were processed with FreeSurfer. Group differences were calculated for each protocol and meta-analyzed. Compared with controls, patients with schizophrenia demonstrated smaller bilateral hippocampus, amygdala, thalamus and accumbens volumes as well as intracranial volume, but larger bilateral caudate, putamen, pallidum and lateral ventricle volumes. We replicated the rank order of effect sizes for subcortical volumetric changes in schizophrenia reported by the ENIGMA consortium. Further, we revealed leftward asymmetry for thalamus, lateral ventricle, caudate and putamen volumes, and rightward asymmetry for amygdala and hippocampal volumes in both controls and patients with schizophrenia. Also, we demonstrated a schizophrenia-specific leftward asymmetry for pallidum volume. These findings suggest the possibility of aberrant laterality in neural pathways and connectivity patterns related to the pallidum in schizophrenia.

Figure 1

Flow chart of protocol selection into the current meta-analytic study. HC, healthy control; MRI, magnetic resonance imaging; SZ, schizophrenia.

Figure 2

Meta-analytic overall effect sizes (Cohen's d)±standard errors for subcortical regional volume differences between patients with schizophrenia and healthy controls. Results of the van Erp et al. study from ENIGMA-SZ (blue-colored bars) and those of the current study from COCORO (pink-colored bars) are merged. Between-group differences in subcortical volumes adjusted for age, sex and intracranial volume, as well as differences in intracranial volume adjusted for age and sex, were included into the meta-analysis and overall differences were obtained. The corresponding forest plots are described in Supplementary Figures 3a–q. An overall effect size was calculated as the ratio of the overall difference to the pooled standard deviation. A positive effect size means that patients with schizophrenia had larger volumes than healthy controls. accumb, accumbens; amyg, amygdala; caud, caudate; COCORO, Cognitive Genetics Collaborative Research Organization; ENIGMA, Enhancing Neuro Imaging Genetics through Meta-Analysis; ENIGMA-SZ, ENIGMA Schizophrenia Working Group; hippo, hippocampus; ICV, intracranial volume; L, left; LatVent, lateral ventricle; pal, pallidum; put, putamen; R, right; thal, thalamus.

Figure 3

Within-group meta-analytic overall effect sizes (Cohen's d)±standard errors for laterality indices (LIs) of subcortical regional volumes in healthy controls (white bars) and in patients with schizophrenia (gray bars). An LI was defined as the ratio [(left−right)/(left+right)]. In each group, mean LIs and their standard errors were entered into the meta-analysis and an overall mean was obtained. The corresponding forest plots are described in Supplementary Figures 4a–h and 5a–h. An overall effect size for LIs was calculated as the ratio of the overall mean LIs to the overall standard deviation. A positive effect size demonstrates a leftward asymmetry. accumb, accumbens; amyg, amygdala; caud, caudate; hippo, hippocampus; LatVent, lateral ventricle; pal, pallidum; put, putamen; thal, thalamus.