Table 1 highlights the conflicting results reported in the literature concerning sexual dimorphism in the size of neuroanatomical structures. To date, there is no consensus whether sexual dimorphism in the size of neuroanatomical structures exists, or if such differences are caused by differences in ICV correction methods between the studies. In studies with two healthy groups, comparing for example men and women, the residuals method and the ANCOVA method with only ICV as covariate are identical ( O'brien et al., 2011 Nordenskjöld et al., 2015). The three most frequently used ICV-correction methods are the ICV-proportions, the ICV-residuals and the ICV as a covariate of no interest, ANCOVA, method ( O'brien et al., 2011).
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These automated methods have been compared to manual delineation and found to have acceptable agreement ( Keihaninejad et al., 2010 Hansen et al., 2015 Malone et al., 2015).
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While manual delineation is considered the criterion standard, it is labor-intensive and automatic methods implemented in software like FreeSurfer and SPM are frequently used. There are several ways of estimating ICV. When investigating sex differences in volume of neuroanatomical structures, it is customary to correct for variations in intracranial volume (ICV) since corrected neuroanatomical volumes are believed to be more valid than absolute volumes in describing structure-function relationships ( Sanfilipo et al., 2004). Investigating the impact of sex on brain structure is thus important to improve our understanding of both the normal brain and brain pathologies. In such sexually dimorphic brain diseases, a potential sex-specific protective agent might exist that could lead to future therapies ( Mccarthy et al., 2012). There are well-known sex differences in the prevalence, age-of-onset and severity of several brain-related diseases, including Alzheimer's disease, stroke, multiple sclerosis, bipolar- and autistic disorder, depression, Parkinson's disease and schizophrenia ( Iacono and Beiser, 1992 Hirtz et al., 2007 American Psychiatric Association, 2013). In conclusion, sex plays a minor role for neuroanatomical volume differences most differences are related to ICV. The findings in the current study explain some of the considerable variation in the literature on sexual dimorphisms in neuroanatomical volumes. Adding additional sexual dimorphic covariates to the ANCOVA gave opposite results of those obtained in the ICV-matched subsample or with the residuals method. The proportions method suffered from systematic errors due to lack of proportionality between ICV and neuroanatomical volumes, leading to systematic mis-assignment of structures as either larger or smaller than their actual size. The residuals and ANCOVA methods were most effective at removing the effects of ICV. Sex differences were detected in a few structures amygdala, cerebellar cortex, and 3rd ventricle were larger in men, but the effect sizes were small. Most sex differences were related to volume scaling with ICV, independent of sex. In addition, sex-specific subsamples were created to investigate whether differences were an effect of head size or sex. Our aims were to investigate presence of sexual dimorphism in 18 neuroanatomical volumes unrelated to ICV-differences by using a large ICV-matched subsample of 304 men and women from the HUNT-MRI general population study, and further to demonstrate in the entire sample of 966 healthy subjects, which of the ICV-correction methods gave results similar to the ICV-matched subsample. However, these different methods give contradictory results with regard to presence of sex differences. Commonly applied methods are the ICV-proportions, ICV-residuals and ICV as a covariate of no interest, ANCOVA. When investigating volume differences in neuroanatomical structures, corrections for variation in ICV are used.
To date, there is no consensus whether sexual dimorphism in the size of neuroanatomical structures exists, or if such differences are caused by choice of intracranial volume (ICV) correction method. Olav's University Hospital, Trondheim, Norway
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