Intracranial volume normalization methods: Considerations when investigating gender differences in regional brain volume

Abstract Intracranial volume (ICV) normalization of regional brain volumes ( v ) is common practice in volumetric studies of the aging brain. Multiple normalization methods exist and this study aimed to investigate when each method is appropriate to use in gender dimorphism studies and how differences in v are affected by the choice of method. A new method based on weighted ICV matching is also presented. Theoretical reasoning and simulated experiments were followed by an evaluation using real data comprising 400 subjects, all 75 years old, whose ICV was segmented with a gold standard method. The presented method allows good visualization of volume relation between gender groups. A different gender dimorphism in volume was found depending on the normalization method used for both simulated and real data. Method performance was also seen to depend on the slope ( B ) and intercept ( m ) from the linear relation between v and ICV ( v = B · ICV + m ) as well as gender distribution in the cohort. A suggested work-flow for selecting ICV normalization method when investigating gender related differences in regional brain volume is presented.