Unstable brain networks may drive multiple sclerosis fatigue

Brain network instability appears to be associated with fatigue in multiple sclerosis (MS) patients -- independent of struc­tural brain damage, according to a study published March 8 in Human Brain Mapping.

The findings could help clinicians "gain new insights into the complex pathology of MS-related fatigue," wrote a group led by Stefanie Hechenberger, PhD, of the Medical University of Graz in Austria.

Fatigue affects between 36.5% and 78% of people with MS and can dramatically impair their daily lives, the researchers noted. It's generally understood that brain regions continuously reconfigure how they communicate within distinct networks (this phenomenon is known as time-varying reconfigurations, or temporal changes in functional connectivity) and that irregular time-varying reconfigurations may contribute to the perception of fatigue in MS patients, the team explained. But neurobiological mechanisms underlying fatigue remain poorly understood.

To address the knowledge gap, Hechenberger and colleagues conducted a study that included 155 people with MS and 48 healthy controls. All participants underwent resting-state functional MRI exams as well as clinical and neuropsychological assessments. The researchers evaluated participants' fatigue using the "Fatigue Scale for Motor and Cognitive Function." They also tracked time-varying connectivity, "promiscuity" (i.e., how many networks a brain region is assigned to relative to the total number of networks), flexibility (i.e., how often a region changes its network assignment over time), cohesion (i.e., how many reconfigurations occur jointly with another region), and disjointedness (i.e., how many reconfigurations occur independently).

The team reported the following:

• 57% of individuals with MS reported experiencing at least mild total fatigue (motor, 60%; cognitive, 57%).
   
• Higher total fatigue was correlated with greater global promiscuity (Pearson correlation coefficient [r] = 0.21, p = 0.032) and disjointedness (r = 0.24, p = 0.008).
   
• Higher motor fatigue was associated with greater global promiscuity (r = 0.25, p = 0.008), flexibility (r = 0.21, p = 0.032), and disjointedness (r = 0.28, p
   
• Network-level analyses in individuals with MS revealed that higher total (r = 0.25, p = 0.016) and motor (r = 0.25, p = 0.016) fatigue were associated with greater limbic network promiscuity.
   
• No significant correlations were found for cognitive fatigue in individuals with MS, or for total, motor, and cognitive fatigue in healthy controls (all, p  > 0.05).
   
• Elevated levels of fatigue -- particularly motor fatigue -- in individuals with MS showed association to more unstable network reconfigurations, particularly of regions in the limbic network, "possibly reflecting dysfunctional reward processing," the authors wrote.

"Notably, these associations were primar­ily driven by motor fatigue, reflecting the fact that total fatigue comprises both motor and cognitive components," the investigators explained.

Further research is needed, Hechenberger and colleagues wrote.

"While this suggests a potential role of network reconfigurations in MS-related fatigue, further studies are needed to confirm these findings," they concluded.

Access the full study here.