Left dorsomedial prefrontal cortex hyperactivation reflects early compensation for emerging social cognition difficulties in multiple sclerosis

Abstract

Social cognition (SC) has emerged as a relevant neurocognitive domain in people with Multiple Sclerosis (pwMS), given its impact on everyday functioning. However, the neural mechanisms supporting SC performance in pwMS remain underexplored, highlighting the need for ecologically valid assessment paradigms capable of capturing both behavioral and neural aspects of social-cognitive functioning. In this study, we addressed this gap by investigating the clinical application of an fMRI-adapted version of the Edinburgh Social Cognition Test (ESCoT) to explore the neural correlates of SC functioning in pwMS. In total, 59 subjects (27 pwMS, mean EDSS = 3.74, and 32 healthy controls) were enrolled in this study and underwent a comprehensive neuropsychological assessment, including SC tests, and the fMRI-adapted version of the ESCoT. No significant between-group differences were observed during the fMRI task performance. Across groups, the paradigm elicited activation within a network involving the bilateral middle temporal poles, left dorsomedial prefrontal cortex, and precuneus, regions consistently implicated in social-cognitive processing. Within the pwMS group, a significant association was identified between neural activation and behavioral SC performance (rho = −0.447, p  = 0.032), linking poorer SC performance with greater activation of the left dorsomedial prefrontal cortex. The findings support the applicability of the ESCoT as an ecologically valid neuropsychological paradigm for capturing the neural processes underlying SC abilities in a clinical population. The observed relationship suggests that increased activation of an executive neural hub may support SC proficiency in pwMS, potentially reflecting an early compensatory strategy.