In this study, we investigated how functional inter-hemispheric connectivity relates to structural CC damage and clinical disability in MS. We found that decreased sHIC, generally in posterior cortical areas, correlates with structural abnormalities in the posterior CC, cognitive dysfunction, and physical disability. We also showed that MS participants with higher sHIC may have some preserved clinical function as measured by BVMT and EDSS, despite CC damage. These results support our hypothesis that callosal damage is associated with alterations in sHIC that contribute to disability.
Our results demonstrated that sHIC is significantly different in MS compared to HC participants. The patterns of sHIC observed in the MS and HC group average correlation maps indicate that inter-hemispheric connectivity was strongest in somatomotor and visual cortices, replicating previous work done by our lab and others (Stark et al., 2008; Tobyne et al., 2016; Zhou et al., 2013). We found that these regions were especially vulnerable to alterations in sHIC in participants with MS. sHIC was globally lower in the MS group, with the largest local reductions occurring in primary motor, somatosensory, visual, cuneus, and temporal cortical areas. While previous studies have also found reduced homologous connectivity in these regions (Lowe et al., 2008; Zhou et al., 2013), they did not demonstrate group differences in precentral, paracentral, superior frontal, and superior parietal cortical areas. Our more robust detection of group differences may be partly due to the superior accuracy of surface-based registration in comparison to volume-based registration methods (Fischl et al., 2008). It is notable that there were no cortical areas with significantly increased sHIC in the MS group. This is in contrast to other studies that have observed complex patterns of both increased and decreased functional connectivity when evaluating inter-hemispheric or network differences in MS and HC groups (Pasqua et al., 2020; Tona et al., 2014; Zhou et al., 2013). Our findings are consistent with the interpretation that callosal damage reduces transmission and synchrony between homologous regions.
In an unbiased general linear model, we found a significant relationship between increased EDSS scores and reduced sHIC in various clusters located in somatomotor cortex. These clusters also roughly overlapped with those observed in primary somatosensory cortex from the MS versus HC group difference analysis. Because inter-hemispheric connectivity tends to be highest in primary sensory regions, sHIC may be a sensitive tool to better understand sensory dysfunction in MS. While we did not observe any significant associations between global homologous connectivity and clinical disability, lower posterior sHIC did correlate with cognitive impairment, as measured by BVMT, PASAT, and SDMT. We also found that impaired performances on BVMT, PASAT, SDMT, 25-foot walk, and 9-hole peg test were associated with lower sHIC in many cortical regions, particularly in the parietal and occipital lobes. There were no cortical regions for which higher sHIC correlated with disability. Overall, our results support the hypothesis that reduced inter-hemispheric connectivity is predictive of poor clinical outcomes.
We found that the structure-function relationship between CC axonal integrity and sHIC was most evident in the posterior CC. This may be due to the anterior to posterior gradient previously observed by Tobyne et al. (2016) in a large healthy control dataset, in which posterior nodes of multiple functional networks generally had higher sHIC than the anterior regions. This phenomenon may help explain the lack of significant correlations between diffusion measures in the other four segments of the CC and the sHIC extracted from their more anterior cortical connections. While the CC is a major white matter bundle connecting the two hemispheres, our tissue microstructure measures did not account for potential changes in hemispheric white matter lateral to the CC. We found that FA and restricted volume fraction in the posterior CC correlated with global sHIC, posterior sHIC, and local sHIC extracted from individual regions in parietal, temporal, and occipital cortex. These results support findings from Zhou et al. (2013), who reported no significant correlations between VHMC and FA for CC segments 1–4, but did find a positive correlation between occipital VHMC and mean FA in the posterior CC (segment 5) in participants with MS. Our results build upon our previous findings that CC atrophy correlates with global sHIC (Tobyne et al., 2016) by adding more specific outcomes for axonal pathology derived from multi-compartmental modeling of the diffusion MRI signal.
Although sHIC correlated with restricted volume fraction, it was not strongly associated with axon density and apparent axon diameter in the CC. It is notable that while the correlations between sHIC and these axonal imaging measures failed to reach statistical significance after controlling for age and gender, they trended in a meaningful direction. High apparent axon diameter (a marker of damage due to the vulnerability of small diameter axons) and low axon density in the CC have been observed in previous high-gradient diffusion MRI studies of MS (Huang et al., 2019; Huang et al., 2016) and trended with reduced sHIC in many cortical regions. While not statistically significant, our results suggest that it may be useful to evaluate these metrics longitudinally and in a larger group of people with MS. Of the diffusion metrics we investigated in the CC, FA and restricted volume fraction were most highly correlated with inter-hemispheric connectivity. This is consistent with previous studies that looked at FA in the CC. Zhou et al. (2013) found that global VMHC correlated with average FA of the entire CC and Lowe et al. (2008) found that decreased inter-hemispheric functional connectivity was associated with decreased FA in transcallosal white matter, but both of these results were only significant in combined MS and HC groups. Using sHIC, we demonstrated this relationship between homologous connectivity and CC damage in the MS group alone.
It is well established that CC damage contributes to clinical disability in MS, however it has been unclear what role inter-hemispheric functional connectivity plays in this relationship. We found that higher levels of sHIC may attenuate the effects of structural CC damage on disability. This was demonstrated through a post-hoc investigation in the posterior CC, looking at restricted volume fraction, FA, and posterior sHIC due to their prior significance. We found that in MS participants with higher average sHIC, alterations in CC microstructure were less associated with clinical impairment, as measured by EDSS and BVMT scores. Increased functional connectivity in MS is a complex phenomenon that has been associated with both clinical improvement (Fuchs et al., 2019; Penner & Aktas, 2017; Sumowski et al., 2013) and decline (Hawellek et al., 2011; Rocca & Filippi, 2017). In this context, high measures of sHIC might indicate that inter-hemispheric functional networks are more adaptable or resilient to microstructural damage in the CC. This compensatory effect may help to preserve cognitive and physical ability. This is consistent with previous studies which have found that MS participants with more normal patterns of default mode network activity were more protected against atrophy-related memory impairment (Sumowski et al., 2013), and MS participants with preserved functional connectivity in cognitive networks maintained cognitive capacity despite grey matter atrophy and white matter tract disruption (Fuchs et al., 2019). We also found that global sHIC for MS participants positively correlated with years of education, which has generally been thought to contribute to “brain reserve” in neurodegenerative disorders (Nithianantharajah & Hannan, 2009). This suggests that environmental factors like education may help preserve inter-hemispheric functional connectivity and prevent progression of disability.
This study was conducted on a group of participants with relapsing-remitting and progressive MS. The sample size of the progressive MS subgroup was too small to perform a meaningful sub-analysis. While combining these groups provided more statistical power, it limits the conclusions for specific MS phenotypes. Additionally, the cross-sectional nature of this study helps reveal associations between sHIC, CC damage, and disability, but a longitudinal study would be necessary to determine if sHIC plays a causal role in preserving clinical function as structural damage accumulates in the brain.
Although sHIC improves spatial accuracy, the technique is limited to the cortical surface. Therefore, the relevant effects of inter-hemispheric connectivity in subcortical and cerebellar regions are not considered. Future work to expand the symmetric template to include subcortical structures would alleviate this issue. Similarly, our analysis of structural damage was limited to diffusion measures in the CC. This fails to account for lesions, atrophy, and microstructural alterations outside of the CC, which may influence inter-hemispheric connectivity