Sex is a defining feature of neuroimaging phenotypes in major brain disorders

Sex is a biological variable that contributes to various elements of brain and behavior in clinical and non-clinical samples. In clinical samples, several studies show sex differences in disease risk, prevalence, and expression of clinical symptoms, yet sex differences in MRI outcomes are still understudied. Here we review the existing literature on sex differences in brain structure in normative samples and in 14 distinct psychiatric and neurological disorders. We discuss commonalities and sources of variance in study designs, analysis procedures, disease subtype effects, and the impact of these factors on MRI interpretation. Lastly, we identify key problems in the neuroimaging literature on sex differences and offer potential recommendations to address current barriers and optimize rigor and reproducibility. In particular, we emphasize the importance of large-scale neuroimaging initiatives such as the Enhancing NeuroImaging Genetics through Meta-Analyses (ENIGMA) consortium, the UK Biobank, Human Connectome Project, and others to provide unprecedented power to evaluate sex-specific phenotypes in major brain diseases.