Hemispheric lateralization abnormalities of the white matter microstructure in patients with schizophrenia and bipolar disorder

Abstract

Background: Hemispheric lateralization of the brain occurs during development and underpins specialized functions. It is posited that aberrant neurodevelopment leads to abnormal brain lateralization in individuals with psychotic illnesses. Here, we sought to examine whether white matter hemispheric lateralization is abnormal in individuals with the psychotic spectrum disorders of schizophrenia and bipolar disorder.

Methods: We examined the white matter microstructure lateralization in patients with schizophrenia, bipolar disorder with psychotic features and healthy controls by measuring the laterality indices of fractional anisotropy (FA) and mean diffusivity (MD). We also correlated the laterality indices with clinical measures.

Results: We included 150 patients with schizophrenia, 35 with bipolar disorder and 77 healthy controls in our analyses. Shared FA lateralization abnormalities in patients with schizophrenia and bipolar disorder were found in the cerebral peduncle and posterior limb of internal capsule, with more extensive abnormalities in patients with bipolar disorder than in those with schizophrenia. The shared MD lateralization abnormalities were more widespread, extending to the subcortical, frontal-occipital, limbic and callosal tracts, with patients with bipolar disorder showing greater abnormalities than patients with schizophrenia. While lateralization was decreased in patients with schizophrenia, the lateralization was reversed in those with bipolar disorder, underpinned by the more pronounced microstructural abnormalities in the right hemisphere. The loss of FA lateralization in patients with schizophrenia was associated with lower quality of life and psychosocial functioning.

Limitations: Owing to the cross-sectional study design, we cannot confirm whether the lateralization abnormalities are neurodevelopmental or a consequence of psychosis onset or chronicity.

Conclusion: Shared and distinct white matter lateralization abnormalities were found in patients with schizophrenia and bipolar disorder. In distinct regions of abnormalities, the lateralization was attenuated in patients with schizophrenia and reversed in those with bipolar disorder.

Fig. 1

White matter microstructural abnormalities in patients with schizophrenia (SZ) and bipolar disorder (BD). Between-group comparisons revealed that (A) compared with healthy controls (HC), patients with schizophrenia exhibited reduced fractional anisotropy (FA) that is widespread throughout the frontal, limbic, subcortical and parietal/occipital regions, and more circumscribed increased mean diffusivity (MD) in the right subcortical and frontal/occipital tracts. (B) Compared with healthy controls, patients with BD showed reduced FA that is widely distributed throughout the brain and increased MD in commissural fibres and right association fibres. (C) Compared with patients with schizophrenia, those with BD showed reduced FA in the commissural, subcortical and right association fibres as well as increased MD in the right projection and association fibres (internal capsule, external capsule, corona radiata and superior longitudinal fasciculus). Results were thresholded at p < 0.05 (using a threshold-free cluster enhancement method that controls for family-wise error) and thickened with the “tbss_fill” command (FSL) for better visibility.

Fig. 2

White matter laterality index (LI) abnormalities in patients with schizophrenia (SZ) and bipolar disorder (BD). Between-group comparisons revealed (A) greater fractional anisotropy (FA) LI in the cerebral peduncle and posterior limb of the internal capsule, and smaller mean diffusivity (MD) LI in patients with schizophrenia along similar regions as well as the external capsule and superior longitudinal fasiculus compared with healthy controls (HC); (B) greater FA LI and smaller MD LI in patients with BD compared with controls in the callosal, limbic, corticospinal and superior longitudinal fasicular tracts; and (C) greater FA LI and smaller MD LI in patients with BD than in those with schizophrenia in similar tracts. Results were thresholded at p < 0.05 (using a threshold-free cluster enhancement method that controls for family-wise error) and thickened with the “tbss_fill” command (FSL) for better visibility. We then parsed the white matter regions found to show FA and MD lateralization differences between patients with schizophrenia and BD. (D) We measured the within-group average of FA values in the left and right hemispheres. The mean FA values of the regions (cerebral peduncle, internal capsule, superior corona radiata, and superior longitudinal fascisculus) are shown in the coloured bars (controls in green, schizophrenia group in blue and BD group in orange). Patients with BD demonstrated decreased FA in the right hemisphere compared with controls and patients with schizophrenia. In addition, we compared the mean FA LI among the 3 groups and found a pattern of reversed LI in patients with BD compared with controls and patients with schizophrenia. (E) The within-group averaged MD values of the regions (cerebral peduncle, internal capsule, external, corona radiata, fornix/stria terminalis, and superior longitudinal fasciculus) in the left and right hemisphere of the different groups are shown. Patients with BD showed decreased MD in the left hemisphere and increased MD in the right hemisphere compared with controls and patients with schizophrenia. In addition, the mean MD LI among the groups are compared. Overall, patients with schizophrenia showed attenuated MD LI compared with controls. Conversely, patients with BD showed reversed FA and MD LI. The mean and standard deviation of each group are presented by the bar charts. ^*p < 0.05; ^**p < 0.01; ^*** p < 0.001.

Fig. 3

Indices of white matter lateralization are associated with reduced psychosocial functioning and quality of life (QOL) in patients with schizophrenia. Whole-brain voxel-wise regression of white matter laterality index (LI) indicated a correlation between loss of FA lateralization (i.e., increased FA LI) with poorer (A) self-rated QOL in physical health, (B) QOL in psychological well-being and (C) clinician-rated global assessment of functioning (GAF). The top row presents brain regions in which white matter LI correlated with clinical scores, thresholded at p < 0.05 (using a threshold-free cluster enhancement method that controls for family-wise error). Regions were thickened with the “tbss_fill” (FSL) command for better visibility. Scatter plots illustrate the associations between clinical scores and FA laterality indices averaged across the voxels in regions (blue) in patients with schizophrenia.