Metabolic dysfunction in multiple sclerosis: Elevated lactate and impaired post-exercise creatine response in the anterior cingulate cortex

Background: Multiple Sclerosis (MS) is characterised by altered brain metabolism and increased chronic perceived fatigue. However, the relationship between brain metabolites, fatigue, and physical task effects in MS remains unclear. This study investigated brain metabolite concentrations (glutamate + glutamine (Glx), lactate, and total creatine (tCr)) in the anterior cingulate cortex (ACC), a region involved in interoceptive processing and fatigue perception, before and after a physical task.

Methods: Twenty-two people with MS (pwMS) and 22 matched controls underwent Magnetic Resonance Spectroscopy before and after fatiguing isometric wrist extension tasks. Perceptual measures of state fatigue and effort were recorded. Linear mixed models analysed group differences and task-induced metabolite changes.

Results: PwMS showed higher ACC lactate concentrations than controls at rest and post-exercise (F = 7.08, p = 0.011, 95% CI[0.033, 0.228]). No significant Glx differences were observed. A significant group × exercise interaction for tCr occurred (F = 4.63, p = 0.037, 95% CI[0.027, 0.581]), with tCr decreasing post-exercise in controls (t = 3.09, p = 0.02) but remaining stable in pwMS. Metabolite concentrations did not correlate with baseline fatigue measures in either group. Changes in lactate correlated moderately with perceived effort in pwMS only (r = 0.51, p = 0.04).

Conclusions: This study provides novel evidence of metabolic differences in pwMS, characterised by elevated lactate and stable post-exercise tCr, suggesting altered energy metabolism potentially linked to mitochondrial dysfunction. While these metabolic alterations did not directly correlate with perceived fatigue, they may contribute to the complex pathophysiology of MS-related fatigue.