Preserved α2 oscillations underpin reserve-related resilience of semantic verbal fluency in multiple sclerosis.

Introduction: Cognitive reserve (CR) is associated with better cognitive outcomes in people with multiple sclerosis (PwMS), yet the neurophysiological factors mediating this relationship remain poorly understood. In this context, alpha ( Methods: Sixty-four PwMS and 46 age- and sex-matched healthy controls underwent resting-state electroencephalography to compute cortical global spectral power. CR was assessed using the Cognitive Reserve Index questionnaire, and verbal fluency was evaluated with the semantic and phonemic verbal fluency tests. Regression and mediation analyses examined associations among CR, spectral power, and verbal fluency, adjusted for demographic, clinical, and patient-reported factors. Exploratory moderated mediation analyses assessed potential variation across levels of disability and perceived disease impact. Results: PwMS exhibited reduced upper α power (α2; 10-13 Hz) compared with healthy controls. α2 power statistically mediated the relationship between CR and SVF, such that individuals with higher CR showed α2 activity closer to healthy norms, which in turn was associated with better SVF performance. No such associations were observed for phonemic verbal fluency, and this mediation was not replicated in healthy controls. Regional analyses indicated that these indirect effects were most evident in bilateral frontal, left central, and right parietal regions. The mediation was not formally moderated by disease burden, although conditional indirect effects suggested the CR → α2 → SVF path was present at moderate and moderate-to-high levels of physical disability and perceived disease impact, respectively. Discussion: These findings suggest that preserved α2 oscillatory activity is a candidate neurophysiological mechanism linking CR and semantic-language functioning in PwMS. To the best of our knowledge, this is the first study in MS to jointly examine CR, oscillatory preservation, and SVF within a single analytical framework, advancing current understanding of the neural basis of reserve-related resilience in PwMS. Clinical trial registration: ClinicalTrials.gov, identifier NCT04806568.