Intracranial volume (ICV) is usually treated as a global or nuisance covariate in almost all volumetric studies of schizophrenia. However, validation for this analytic method has seldom been accomplished. In this study, we aimed to determine the effects of ICV on gray matter (GM) and white matter (WM) volumes. Sixty-three patients with schizophrenia and sixty normal controls were recruited; and high resolution T1 weighted images were obtained by 3T-MRI. After segmentation and normalization of the images into GM, WM, and cerebrospinal fluid (CSF), multiple regression analyses of global GM and WM volumes were performed using explanatory variables such as diagnosis, ICV, and diagnosis-ICV interaction. In addition, associations between regional GM and WM volumes with ICV were also investigated using voxel-based morphometry (VBM). No significant interaction between diagnosis and ICV was found for global GM volume, whereas interactions were detected in restricted GM areas using VBM. On the other hand, an interaction between ICV and diagnosis was found in WM not only for regional volumes, but also for global WM volume. The regression slope of global WM volumes against ICV was steeper in patients with schizophrenia than in healthy controls. These results imply that ICV should be carefully evaluated in the analyses of volumetric studies of schizophrenia, especially when analyzing WM volumes.
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