One contribution of 16 to a theme issue 'Multifaceted origins of sex differences in the brain'. Recent years have witnessed an increased attention to studies of sex differences, partly because such differences offer important considerations for personalized medicine. While the presence of sex differences in human behaviour is well documented, our knowledge of their anatomical foundations in the brain is still relatively limited. As a natural gateway to fathom the human mind and behaviour, studies concentrating on the human brain network constitute an important segment of the research effort to investigate sex differences. Using a large sample of healthy young individuals, each assessed with diffusion MRI and a computerized neurocognitive battery, we conducted a comprehensive set of experiments examining sex-related differences in the meso-scale structures of the human connectome and elucidated how these differences may relate to sex differences at the level of behaviour. Our results suggest that behavioural sex differences, which indicate complementarity of males and females, are accompanied by related differences in brain structure across development. When using subnetworks that are defined over functional and behavioural domains, we observed increased structural connectivity related to the motor, sensory and executive function subnetworks in males. In females, subnetworks associated with social motivation, attention and memory tasks had higher connectivity. Males showed higher modularity compared to females, with females having higher inter-modular connectivity. Applying multivariate analysis, we showed an increasing separation between males and females in the course of development, not only in behavioural patterns but also in brain structure. We also showed that these behavioural and structural patterns correlate with each other, establishing a reliable link between brain and behaviour. BackgroundWhile the presence of sex differences in human behaviour and cognition is well documented [1,2], our knowledge of anatomical foundations for such sex differences, specifically in the brain, is still relatively limited. The enigmatic interplay between brain and behaviour, and its modulation by sex, has intrigued scientists, philosophers and the general public for decades. Behavioural differences include, but are not limited to, enhanced motor [3,4] and spatial skills [5,6] in males and improved memory [7,8] and social cognition [9,10] skills in females [11]. These differences may be attributed to the complementary roles that the sexes play in procreation and social structure; however, increasing evidence suggests the presence of corresponding sex differences in brain structure and function [12][13][14][15][16][17], as well as the presence of a strong connection between behaviour and brain structure [12,18]. Thus, relying merely on social and cultural effects to explain sex-induced variance in behaviour seems insufficient. Notably, although sex differences in the brain are present even in childhood [16,17], the

Many of the clinical and behavioral manifestations of traumatic brain injury (TBI) are thought to arise from disruption to the structural network of the brain due to diffuse axonal injury. However, a principled way of summarizing diffuse connectivity alterations to quantify injury burden is lacking. In this study, we developed a connectome injury score, Disruption Index of the Structural Connectome (DISC), which summarizes the cumulative effects of TBI-induced connectivity abnormalities across the entire brain. Forty patients with moderate to severe TBI examined at three months post-injury and 35 uninjured healthy controls (HC) underwent magnetic resonance imaging (MRI) with Diffusion Tensor Imaging (DTI), and completed behavioral assessment including global clinical outcome measures and neuropsychological tests. TBI patients were selected to maximize the likelihood of diffuse axonal injury (DAI) in the absence of large focal brain lesions. We found that hub-like regions, with high betweenness centrality, were most likely to be impaired as a result of diffuse TBI. Clustering of participants revealed a subgroup of TBI patients with similar connectivity abnormality profiles who exhibited relatively poor cognitive performance. Among TBI patients, DISC was significantly correlated with post-traumatic amnesia, verbal learning, executive function, and processing speed. Our experiments jointly demonstrated that assessing structural connectivity alterations may be useful in development of patient-oriented diagnostic and prognostic tools.