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These findings support our interpretation that PPMS does not lead to major topological changes but rather to subtle alterations of the brain network.

For example, they were not able to separate comatose patients from HCs in an f MRI study, while hub regions showed a clear loss in connectivity.

Taking the functional data into account, one might hypothesize that a continuous loss of rich-club connectivity can only be compensated by peripheral connections in the early phase. Critical revision of the manuscript for important intellectual content: J.-P.

However, preliminary data in RRMS indicate that the shift toward more peripheral connectivity is detectable within a time frame of 6 months and might be reduced by an exercise intervention.

These findings support our observation that PPMS affects particularly the regions of the brain with a prominent and integrative role in the structural connectome, whereas peripheral connections are less compromised, preserved, or even rewired due to neurorepair.

A longitudinal study of f MRI connectivity found a compensatory upregulation in early disease stages without relevant disability.

The cross-sectional nature of our study does not allow determining when the shift from rich-club to peripheral connectivity occurs.

S.), University Medical Center Hamburg-Eppendorf, Germany. From the Institut für Neuroimmunologie und Multiple Sklerose (INIMS) (J.-P. Moreover, it is unknown how these functional changes translate into altered structural connectivity.

S.), University Medical Center Hamburg-Eppendorf, Germany. From the Institut für Neuroimmunologie und Multiple Sklerose (INIMS) (J.-P.

Hilgetag), and Department of Diagnostic and Interventional Neuroradiology (S.

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