In this study, we combined two advanced imaging techniques, probabilistic tractography and FreeSurfer cortical surface-based methodology, to perform a comprehensive in vivo assessment of the motor system, including the CST and the PMC, and investigate the contribution of WM and GM damage to disability in MS.
With regard to the WM assessment, we found that patients had significantly lower CST FA than controls, but CST connectivity correlated with EDSS and pyramidal FS score better than CST FA. This suggests that connectivity is a measure complementary to FA. These findings extend previous investigations, which have either assessed the FA along the CST9,44,45
or tested for correlations between connectivity and disability in MS4,6
Furthermore, a recent study that specifically investigated the relationship of MRI abnormalities in the CST with lower limb weakness, revealed a moderate but significant quantitative association between disability and tract-specific MRI changes, in keeping with our results.46
A novelty of our study is that we obtained several measures of the PMC, other than the volume and tested motor-system specific hypotheses. The most interesting results from these analyses are: (i) patients had lower surface area and volume of the precentral cortex than controls; this finding gives insight into the mechanisms of cortical atrophy in MS, indicating that the loss of volume may occur due to the reduction in the surface area rather than in the thickness; (ii) the surface area and curvature of the paracentral cortex correlated with motor disability, being lower in patients with higher pyramidal FS score; (iii) smaller paracentral cortex volume was associated with worse walking ability, as measured by the TWT. These results suggest that new cortical measures of the PMC, such as surface area and curvature, reflect damage that contributes to functionally relevant impairment. These GM measures should, therefore, be used in future studies to quantify clinically relevant abnormalities in cortical morphology in MS.
The potential relationship of these novel measures with the underlying pathological abnormalities known to occur in MS is interesting, and deserves further studies that compare imaging measures with histological findings. Surface area and curvature may reflect changes in cortical architecture due to either intrinsic GM pathology or WM abnormalities. In terms of GM pathology, neuronal loss is the major determinant of cortical atrophy, while focal cortical demyelination is less relevant.47
Importantly, loss of dendritic and axonal projections of the surviving axons also contributes to cortical atrophy.48
It is therefore possible that the reduction in surface area detected in patients when compared with controls is driven by the loss of neurons and dendritic arbors, while the corresponding correlation with disability reflects the functional consequences of these pathological processes. Conversely, it seems more likely that cortical curvature is driven by loss of volume in the underlying WM. However, at present, it is not possible to distinguish between these processes using MRI alone, and it is likely that a combination contributes to the observed changes in cortical measures. An important consideration is that a methodological bias during segmentation/parcellation of the cortex may have contributed to the observed changes in cortical surface and curvature between patients and controls and their correlation with disability. For example, one could hypothesize that the automated definition of specific cortical areas, which uses sulcal and gyral anatomy, would be less accurate in patients than controls, if the cortical surface anatomy in patients is grossly abnormal. However, the results of our cortical segmentation were checked visually for each subject, and were considered to be correct and consistent between groups. Furthermore, it should be noted that the FreeSurfer methodology has been validated in previous studies using phantom and post-mortem material,31–40
and that the results from a large number of studies using this technique for cortical segmentation in vivo
in different patient groups, including MS, appears remarkably reproducible.49–51
With respect to the PMC thickness, we did not find differences between groups, which may be related to the moderate disability of our patients, compared with a previous study.14
However, the patient sample size was small and may well have limited the detection of subtle group differences. On the other hand, the lack of correlation between the PMC thickness and disability is in agreement with another study.12
Further studies are needed to clarify the contribution of focal thinning of the PMC to motor disability.
Our investigation of the relationship between CST and PMC measures in patients gave intriguing results. On the affected side, the surface area of the paracentral cortex increased as tract connectivity decreased, while the opposite was true for the unaffected side, where the surface area increased with increasing tract connectivity. This may imply that a lesion in the CST causes significant structural changes in the morphology of the PMC. Functional MRI studies in MS provide evidence for both inter- and intrahemispheric reorganization of PMC activation,52–54
and our results possibly reflect the structural correlates of this functional adaptation.55
This important issue warrants further investigation: future studies will permit a better understanding of the relationship between (i) the mechanisms of WM and GM damage in specific brain regions and (ii) the mechanisms of functional and structural adaptation in the motor system in MS. In particular, our understanding of the way in which WM pathology drives cortical atrophy and reorganization will benefit greatly from longitudinal studies, which will assess cortical measures, including the newly developed techniques that are introduced here, in relation to functionally relevant WM lesions over time.
Our study has some limitations. First, our sample size was relatively small, although carefully selected to represent patients with a previous episode of hemiparesis. It is possible that the sample size may be too small to detect a true finding, and, therefore, some of our non-significant results could be false negatives. For example, as shown on , connectivity in the CST of patients decreases by as much as 17.8% when compared to controls, though this remains non-significant; indeed, the 95% CIs associated with this sample difference were quite wide (−100.9, 832.5). Similarly, we cannot exclude the possibility that some of the non-significant correlations of the MRI measures with disability represent false negative results. In particular, in the case of the non-significant correlations between FA and EDSS or thickness of the PMC and both EDSS and TWT, although the magnitude of the coefficient suggests a negative association between FA or cortical thickness and disability, the corresponding 95% CIs were again quite wide. Therefore, in the future, larger studies will be required to confirm the results reported here. Second, a large number of statistical tests (about 90) were performed, without formal correction for multiple comparisons. Nevertheless, for an alpha level of 0.05, one would expect on average 4.5 out of 90 false positive results. However, we reported 10 significant results for a p
-value of ≤0.05, making a type I error very unlikely to account for all these significant results. Furthermore, this is a hypothesis-driven rather than an exploratory study, making the need for multiple comparison corrections less relevant.56
Notwithstanding these limitations, the present study has demonstrated the utility of applying advanced MRI to assess structural damage in the WM and GM of the motor system in MS and provide possible markers of structural damage that is clinically relevant. Imaging functional systems that are important for disability, and, in particular, the assessment of both the WM and GM damage within these systems, may emerge as a reliable method to test specific hypotheses in MS and in other neurological diseases.