Heterogeneity and Homogeneity of Regional Brain Structure in Schizophrenia: A Meta-analysis

Abstract

Importance: Schizophrenia is associated with alterations in mean regional brain volumes. However, it is not known whether the clinical heterogeneity seen in the disorder is reflected at the neurobiological level, for example, in differences in the interindividual variability of these brain volumes relative to control individuals.

Objective: To investigate whether patients with first-episode schizophrenia exhibit greater variability of regional brain volumes in addition to mean volume differences.

Data sources: Studies that reported regional brain volumetric measures in patients and controls by using magnetic resonance imaging in the MEDLINE, EMBASE, and PsycINFO databases from inception to October 1, 2016, were examined.

Study selection: Case-control studies that reported regional brain volumes in patients with first-episode schizophrenia and healthy controls by using magnetic resonance imaging were selected.

Data extraction and synthesis: Means and variances (SDs) were extracted for each measure to calculate effect sizes, which were combined using multivariate meta-analysis.

Main outcomes and measures: Relative variability of regional brain volumetric measurements in patients compared with control groups as indexed by the variability ratio (VR) and coefficient of variation ratio (CVR). Hedges g was used to quantify mean differences.

Results: A total of 108 studies that reported measurements from 3901 patients (1272 [32.6%] female) with first-episode schizophrenia and 4040 controls (1613 [39.9%] female) were included in the analyses. Variability of putamen (VR, 1.13; 95% CI, 1.03-1.24; P = .01), temporal lobe (VR, 1.12; 95% CI, 1.04-1.21; P = .004), thalamus (VR, 1.16; 95% CI, 1.07-1.26; P < .001), and third ventricle (VR, 1.43; 95% CI, 1.20-1.71; P < 1 × 10-5) volume was significantly greater in patients, whereas variability of anterior cingulate cortex volume was lower (VR, 0.89; 95% CI, 0.81-0.98; P = .02). These findings were robust to choice of outcome measure. There was no evidence of altered variability of caudate nucleus or frontal lobe volumes. Mean volumes of the lateral (g = 0.40; 95% CI, 0.29-0.51; P < .001) and third ventricles (g = 0.43; 95% CI, 0.26-0.59; P < .001) were greater, whereas mean volumes of the amygdala (g = -0.46; -0.65 to -0.26; P < .001), anterior cingulate cortex (g = -0.26; 95% CI, -0.43 to -0.10; P = .005), frontal lobe (g = -0.31; 95% CI, -0.44 to -0.19; P = .001), hippocampus (g = -0.66; 95% CI, -0.84 to -0.47; P < .001), temporal lobe (g = -0.22; 95% CI, -0.36 to -0.09; P = .001), and thalamus (g = -0.36; 95% CI, -0.57 to -0.15; P = .001) were lower in patients. There was no evidence of altered mean volume of caudate nucleus or putamen.

Conclusions and relevance: In addition to altered mean volume of many brain structures, schizophrenia is associated with significantly greater variability of temporal cortex, thalamus, putamen, and third ventricle volumes, consistent with biological heterogeneity in these regions, but lower variability of anterior cingulate cortex volume. This finding indicates greater homogeneity of anterior cingulate volume and, considered with the significantly lower mean volume of this region, suggests that this is a core region affected by the disorder.

Figure 1.. Forest Plot Showing Effect Sizes for Variability Ratio (VR) of Regional Brain Volumes in Schizophrenia

The VR was significantly increased in the lateral and third ventricles, temporal lobe, thalamus, and putamen, indicating greater variability in the volumes of these structures in patient groups relative to controls. In contrast, the VR was significantly reduced in the anterior cingulate cortex (ACC), indicating lower variability in the volume of this region in patient groups.

Figure 2.. Forest Plot Showing Effect Sizes for Mean-Scaled Variability in Regional Brain Volumes in Schizophrenia

The coefficient of variation ratio (CVR) was significantly increased in the amygdala, hippocampus, putamen, temporal lobe, thalamus, and third ventricle, indicating greater variability in the volumes of these structures in patient groups relative to controls, after accounting for group differences in the mean volumes. ACC indicates anterior cingulate cortex.

Figure 3.. Forest Plot Showing Effect Sizes for Mean Differences in Regional Brain Volumes in Schizophrenia

Mean volumes of the third and lateral ventricles were significantly increased, whereas mean volumes were significantly reduced for the thalamus, temporal lobe, hippocampus, frontal lobe, anterior cingulate cortex (ACC), and amygdala in schizophrenia.