The topological changes in rich-club organization provide novel insight into sex-specific effects on white matter connections that underlie a potential network mechanism of sex-based differences in cognitive function

Sex Differences in Anatomical Rich-Club and Structural–Functional Coupling in the Human Brain Network. Shuo Zhao, Gongshu Wang, Ting Yan, Jie Xiang, Xuexue Yu, Hong Li, Bin Wang. Cerebral Cortex, bhaa335, Nov 24 2020. https://doi.org/10.1093/cercor/bhaa335

Abstract: Structural and functional differences between the brains of female and male adults have been well documented. However, potential sex differences in the patterns of rich-club organization and the coupling between their structural connectivity (SC) and functional connectivity (FC) remain to be determined. In this study, functional magnetic resonance imaging and diffusion tensor imaging techniques were combined to examine sex differences in rich-club organization. Females had a stronger SC-FC coupling than males. Moreover, stronger SC-FC coupling in the females was primarily located in feeder connections and non–rich-club nodes of the left inferior frontal gyrus and inferior parietal lobe and the right superior frontal gyrus and superior parietal gyrus, whereas higher coupling strength in males was primarily located in rich-club connections and rich-club node of the right insula, and non-rich-club nodes of the left hippocampus and the right parahippocampal gyrus. Sex-specific patterns in correlations were also shown between SC-FC coupling and cognitive function, including working memory and reasoning ability. The topological changes in rich-club organization provide novel insight into sex-specific effects on white matter connections that underlie a potential network mechanism of sex-based differences in cognitive function.

Keywords: cognitive function, rich-club organization, SC-FC coupling, sex differences, topological properties

Discussion

We examined changes in the patterns of rich-club organization in structural networks and functional brain dynamics between females and males. The main findings were as follows: 1) We found increased values of the topological properties cost, Eg, Eloc, and strength in male versus female adults. 2) Compared with the male adults, the female adults had a greater strength in the SC-FC coupling. Moreover, the females had a negative correlation between the SC-FC coupling and the cost of the topological properties, whereas the males had a positive correlation between the SC-FC coupling and the cost of the topological properties. 3) Different regions of SC-FC coupling were observed between females and males. A higher SC-FC coupling in the females than males was primarily located in the non-rich-club nodes, including regions of the left IFG and IPL and the right SFG and SPG. A higher SC-FC coupling in the males than females was located not only in the rich-club nodes, including the right INS, but also in non–rich-club nodes, including the left hippocampus and the right PHG. 4) A sex-specific correlation was found between SC-FC coupling in the brain network and cognitive performance. The females had a negative correlation between local SC-FC coupling and working memory, whereas the males had a positive correlation between rich-club SC-FC coupling and reasoning ability. We thus conclude that the pattern differences in the correlations between SC-FC coupling and cognitive function were affected by sex differences, which may help to reveal a potential network mechanism of sex differences in cognitive function.

In this study, when a range of degrees k from 5 to 10 was used, the males had higher rich-club coefficients than the females, which reflected the existence of different rich-club organization in the brain topological properties between females and males. That is, increased effects were found with the topological properties of cost, Eg, Eloc, and strength in the males versus the females. In particular, the strength and cost of feeder and local but not rich-club connections was increased. These findings were consistent with previous studies (e.g., Wang et al. 2019a) that found higher levels of cost, density, and strength among topological properties in males than in females. These differences between males and females exhibited typical rich-club properties, revealing greater global efficiency, local efficiency, and strength in males but a more economical rich-club architecture in females.

Importantly, the present study combined DTI techniques and functional resting-state techniques and found a greater coupling strength in the SC-FC in the females than males. Although previous studies (e.g., Zell et al. 2015; Gur and Gur 2017; Ritchie et al. 2018) have reported differences between males and females in the topological properties of structural connections or functional connections, the present study provides further evidence for sex differences in the relationship between SC and FC coupling, revealing greater SC-FC coupling strength in females than in males. Compared with males, females had greater coupling strength in the rich-club and local but not feeder SC-FC coupling. Moreover, this strength was associated with the cost of topological properties in the rich-club and local coupling. Specifically, the correlation between SC-FC coupling strength and the cost of local connections was negative with females, whereas the correlation between SC-FC coupling strength and the cost of rich-club connections was positive with males. Therefore, the increase in SC-FC coupling in females was mainly concentrated in rich-club and local connections that correspond to more stringent and less dynamic brain function (Honey et al. 2009; van den Heuvel et al. 2009) and influence the cost of rich-club architecture compared to that of males. Previous studies (Collin et al. 2014) have proposed that information integration is influenced by the architecture of neural systems, which may be driven by a potential “trade-off” between cost and communication efficiency, known as the cost-efficiency trade-off of neural circuitry formation. Based on this proposition, the present finding of difference between males and females in SC-FC coupling may contribute to a more accurate understanding of sex differences in the dynamic changes and information integration in brain network structures. Additionally, as previous studies have reported that SC-FC coupling increased with age (Supekar et al. 2010; Grayson et al. 2014) and was disrupted in the context of clinical disease (van den Heuvel et al. 2013; Collin et al. 2017; Wang et al. 2019b; Cao et al. 2020), the present findings might also provide a future direction to examine the age-related changes and disease-related disruptions in SC-FC coupling in different sexes.

Moreover, a difference in SC-FC coupling was found between females and males in the nodes of the rich-club organization. Specifically, greater SC-FC coupling in the females was primarily located in the non-rich-club nodes, including the left IFG and right SFG in the frontal lobe and the left IPL and right SPG in the parietal lobe, whereas greater SC-FC coupling in the males was located not only in the rich-club nodes, including the right INS, but also in non-rich-club nodes, including the left hippocampus and right PHG. All of these regions are the limbic system. The findings were largely consistent with a previous report that the structural properties of these regions were different between females and males. Gong et al. (2009), using diffusion MRI tractography data, revealed a lower efficiency in the IFG in females than males. However, a higher regional efficiency was shown in females than males in the SPG (Gur et al. 1999). Ritchie et al. (2018) also found a larger brain volume in the right superior parietal region in females than males but no difference in the left inferior parietal region, although a greater connectivity in the IPL was reported by Gong et al. (2011). All of these regions are located in the dorsal frontoparietal network and participate in various functions, including spatial attention (Corbetta and Shulman 2002; Fellrath et al. 2016). Additionally, the INS is an important hub region associated with spatial cognition, which exhibited greater connectivity (Gong et al. 2011) but lower FA values (Chou et al. 2011) in males than females. The PHG and hippocampus are located in the limbic system and play an important role in memory. Using the tract-based spatial statistic (TBSS) method, Chou et al. (2010) showed that females had higher FA values in the PHG but lower FA values in the hippocampus. Ritchie et al. (2018) found a higher thickness in the PHG in females, but a higher volume and surface area in males. Based on these findings, our results extend the identification of sex differences to SC-FC coupling. We suggest that the advantage of this approach is the differences in SC-FC coupling in rich-club and non-rich-club nodes between females and males. As previous studies have reported sex differences in cognitive performance, including memory (Harness et al. 2008; Levine et al. 2016), spatial attention and spatial cognition (Vaquero et al. 2004; Levine et al. 2016), we therefore proposed that SC-FC coupling in females and males in the different nodal regions between rich-club and non-rich-club nodes represents submodular organization for specific functional domains that may exhibit optimized patterns, leading to improved performance in corresponding cognitive functions. However, other characteristics, such as brain volume differences, are also likely to account for sex differences in specific cognitive functions.

In this study, we also examined the relationship between SC-FC coupling and cognitive performance in females and males. Specifically, we found a negative correlation between local SC-FC coupling and working memory in the females, whereas a positive correlation was shown between rich-club SC-FC coupling and reasoning ability in the males. Previous studies have reported that males scored significantly higher on reasoning ability (Quereshi and Seitz 1993; Lakin 2013) and that females scored significantly higher on working memory (Harness et al. 2008) in cognitive performance. For example, van der Sluis et al. (2006) reported that males scored higher on reasoning ability, while females scored higher on working memory, on the Dutch WAIS-III. Neuroimaging research has also reported sex differences in cognitive performance, including working memory and reasoning ability. Specifically, a meta-analysis study (Hill et al. 2014) found that males had more activity in a distributed network including parietal regions, while females had activity in more limbic regions including the amygdala and hippocampus, as well as prefrontal regions including the right inferior frontal gyrus. Moreover, one team (Ritchie et al. 2018) showed, using a large sample (2750 females and 2466 males), that sex differences in reasoning ability were associated with brain volume and surface area. The present results extended these findings in the SC-FC coupling in the rich-club organization that showed sex differences, suggesting reduced working memory in females and increased reasoning ability in males was associated with the females having less stringent and more dynamic brain function in the local connections, and the males having more stringent and less dynamic brain function in the rich-club connections. Given the importance of working memory and reasoning ability as pivotal cognitive functions in the intellectual domain, these observations suggest that sex differences in SC-FC coupling linked to reduced working memory and increased reasoning ability are closely related to the intellectual domain, potentially helping to explain how and why males and females differ in intelligence and academic achievement. 

Limitations.

The present study has several limitations that should be acknowledged. First, the sample size of subjects was relatively small. Regarding the limitation of the dataset, it is important to validate our findings by replicating our analyses using a larger sample of subjects. Second, in this study, we analyzed the coupling between SC and FC, which was limited to the connections with nonzero SC and FC. Although a strong FC also exists between regions with indirect SC (Honey et al. 2009), there is currently no way to analyze the associations between FC and indirect SC because of the limitations of the method. The aim of this study was simply to investigate differences in SC-FC coupling between females and males. Future research should examine the indirect connections to analyze the SC-FC coupling between females and males. Furthermore, this study did not sufficiently examine the correlations between the strength of the SC-FC coupling and working memory and reasoning ability in females and males. We used LNS and MR scores to examine the correlations between the strength of the SC-FC coupling and working memory and reasoning ability in females and males. Given that LNS and MR measures only the working memory ability to retrieve auditory information and nonverbal spatial reasoning ability, future studies should also evaluate the relationships between visual working memory and verbal reasoning ability.

In summary, this study found that sex significantly affected the rich-club organization of structural networks in individuals with typical development. Differences in the male versus female adults were shown with the topological properties of cost, Eg, Eloc, and strength. Importantly, a greater coupling strength of the SC-FC in females versus males was observed. Moreover, higher SC-FC coupling in the females was primarily located in the non-rich-club nodes, whereas higher SC-FC coupling in the males was located not only in the rich-club but also in non–rich-club nodes. Our results also found different patterns across sexes in the correlations between SC-FC coupling and cognitive function, including working memory and reasoning ability. Our findings of the topological changes in rich-club organization provide novel insight into sex differences on white matter connections that may underlie a potential network mechanism of sex-based differences in cognitive function.