Aerobic Exercise Induces Functional and Structural Reorganization of CNS Networks in Multiple Sclerosis: A Randomized Controlled Trial

Abstract

Objectives: Evidence from animal studies suggests that aerobic exercise may promote neuroplasticity and could, therefore, provide therapeutic benefits for neurological diseases such as multiple sclerosis (MS). However, the effects of exercise in human CNS disorders on the topology of brain networks, which might serve as an outcome at the interface between biology and clinical performance, remain poorly understood. Methods: We investigated functional and structural networks in patients with relapsing-remitting MS in a clinical trial of standardized aerobic exercise. Fifty-seven patients were randomly assigned to moderate-intensity exercise for 3 months or a non-exercise control group. We reconstructed functional networks based on resting-state functional magnetic resonance imaging (MRI) and used probabilistic tractography on diffusion-weighted imaging data for structural networks. Results: At baseline, compared to 30 healthy controls, patients exhibited decreased structural connectivity that was most pronounced in hub regions of the brain. Vice versa, functional connectivity was increased in hubs. After 3 months, we observed hub independent increased functional connectivity in the exercise group while the control group presented a loss of functional hub connectivity. On a structural level, the control group remained unchanged, while the exercise group had also increased connectivity. Increased clustering of hubs indicates a better structural integration and internal connectivity at the top of the network hierarchy. Conclusion: Increased functional connectivity of hubs contrasts a loss of structural connectivity in relapsing-remitting MS. Under an exercise condition, a further hub independent increase of functional connectivity seems to translate in higher structural connectivity of the whole brain.

Keywords: CNS networks; exercise; multiple sclerosis; neuroplasticity; randomized controlled trial.

Figure 1

Reorganization of functional connectivity. Reorganization of functional connectivity based on the adapted hub disruption index. (A) Baseline: the mean degree of nodes from controls is plotted against the difference between mean baseline values from patients and controls. (B) Mean differences from baseline to month 3 (Δ0–3) in both patient groups are plotted against mean values from healthy controls. (C) Changes of a degree from baseline, node size indicates absolute change while the color indicates the direction.

Figure 2

Reorganization of structural connectivity. Reorganization of structural connectivity based on the adapted hub disruption index. (A) Baseline: the mean strength of nodes from controls is plotted against the difference between mean baseline values from patients and controls. (B) Mean differences from baseline to month 3 (Δ0–3) in both patient groups are plotted against mean values from healthy controls. (C) Changes of strength from baseline, node size indicates absolute change while the color indicates the direction.

Figure 3

Clustering of nodes in structural networks: Baseline and changes. Nodal clustering in structural networks analyzed with the adapted hub disruption index. (A) Baseline: mean differences of the clustering coefficient between patients and controls plotted vs. strength of the nodes as an indicator of the hubness. (B) Mean differences from baseline to month 3 (Δ0–3) are plotted against mean strength from healthy controls for both patient groups. (C) Changes of clustering from baseline, node size indicates absolute change while the color indicates the direction.

Figure 4

Association between graph metrics and clinical scores. Baseline correlations between clinical outcomes and global network metrics (top, A), respectively individual hub disruption (bottom, B). Bright colors indicate p-values < 0.05, asterisks indicate p-values below 0.05 after FDR correction. EDSS, expanded disability status scale; SDMT, symbol digit modality test; VLMT, Verbal learning and memory test; Digit_bw, digit span backward; Digit_fw, digit span forward; TA, tonic alertness; PA, phasic alertness; PASAT, Paced Auditory Serial Addition Test; T25FW = timed 25 foot walk; 6MWT, 6-Minute-Walking-Test; VO2max/kg, VO2 max per kg body weight.