Non-invasive brain stimulation for altering neuro-inflammatory mediators of central fatigue in multiple sclerosis

• Applicants: Dr. Janina Behrens; Dr. Martin Weygandt
• Subject Area: Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 565478101

Multiple sclerosis (MS) is the most frequent chronic and progressive neurological disease, with a rising prevalence that affects nearly three million persons worldwide. In addition to sensorimotor impairment, fatigue is a key symptom of MS which is characterized as a subjective perception ranging from weak feelings of tiredness to an overwhelming and long-lasting sense of exhaustion seriously decreasing one’s ability to carry out daily activities. Consequently, it can impair the social and working life, reduce the financial independence and working time or might even lead to a complete job loss. Despite the considerable burden of MS fatigue, however, not much is known about the pathobiological basis of MS fatigue. In part, this scarcity follows from the multi-faceted nature of fatigue, but even when focusing on one of its most important components, central fatigue (defined as a feeling of constant exhaustion and performance deterioration in tasks requiring self-motivation), the underlying mechanisms are not well understood, and its treatment thus remains difficult. Specifically, although imaging and non-invasive brain stimulation MS studies have confirmed the importance of fronto-striatal brain areas for central fatigue found in non-MS studies, elaborate neurocognitive paradigms allowing to study specific motivational mechanisms processed by these reward regions were studied in MS in a rudimentary form only. Maybe even more surprising given the importance of inflammatory processes for MS and the evidence for a causal impact of inflammation on brain reward processing and fatigue found in other domains, nothing is known about the importance of the interplay between inflammation and brain reward mechanisms for central fatigue in MS. Consequently, we propose an MS research project to study reward-related neural processes for central fatigue in MS, to reveal first insights into the role of the interplay between reward processing and inflammatory mediators, and to test whether these factors are sensitive to transcranial Direct Current Stimulation (tDCS) in 42 persons with relapsing-remitting MS additionally affected by central fatigue and in 42 not additionally affected by this symptom. One half of the persons in each of these groups shall receive tDCS of left dorsolateral prefrontal cortex whereas the other half will receive sham tDCS. Neural reward processing shall be measured with functional MRI tasks specifically designed for this purpose and inflammatory mediators with in-depth proteomic methods. This will be complemented by neuropsychological, clinical, and self-report parameters. By integrating this rich data set within a systems biology framework, the project promises to provide novel insights into the sensitivity of central fatigue and its presumed neuro-inflammatory basis to tDCS and might thus ultimately improve treatment of central fatigue in MS.

• DFG Programme: Research Grants