Background: Modifications in brain function remain relatively unexplored in progressive multiple sclerosis (PMS), despite their potential to provide new insights into the pathophysiology of the disease at this stage.

Objectives: To characterize the dynamics of functional networks at rest in patients with PMS, and the relation with clinical disability.

Methods: Thirty-two patients with PMS underwent clinical and cognitive assessment. The dynamic properties of functional networks, retrieved from transient brain activity, were obtained from patients and 25 healthy controls (HCs). Sixteen HCs and 19 patients underwent a 1-year follow-up (FU) clinical and imaging assessment. Differences in the dynamic metrics between groups, their longitudinal changes, and the correlation with clinical disability were explored.

Results: PMS patients, compared to HCs, showed a reduced dynamic functional activation of the anterior default mode network (aDMN) and a decrease in its opposite-signed co-activation with the executive control network (ECN), at baseline and FU. Processing speed and visuo-spatial memory negatively correlated to aDMN dynamic activity. The anti-couplings between aDMN and auditory/sensory-motor network, temporal-pole/amygdala, or salience networks were differently associated with separate cognitive domains.

Conclusion: Patients with PMS presented an altered aDMN functional recruitment and anti-correlation with ECN. The aDMN dynamic functional activity and interaction with other networks explained cognitive disability.