Beyond GLM: Inter-Subject Variability as a Complementary Approach to Detect Longitudinal Changes in Emotion Processing in Multiple Sclerosis.

Understanding how to reliably capture neural changes induced by treatments in neurological patients remains a major methodological challenge. This issue is particularly evident in the emotional domain-frequently impaired in conditions such as multiple sclerosis (MS) and a key target of rehabilitation-yet not limited to it. Longitudinal neuroimaging studies predominantly rely on group-level analyses (e.g., General Linear Model, GLM), which assume inter-subject homogeneity and treat inter-subject variability (ISV) as noise. Such assumptions may obscure treatment-related neuroplastic changes, especially in domains like emotion processing, where neural responses are intrinsically variable and highly individualized in clinical populations. This study investigates whether modeling ISV can better capture treatment-related neural changes, using emotion-focused rehabilitation as a representative case. We compared GLM with threshold-weighted overlap maps (OMth-w), which quantify spatial consistency across individuals. Thirty healthy controls (HCs) and thirteen people with MS (pwMS) undergoing EMDR for depression performed an emotional fMRI task (pwMS pre/post-treatment). GLM revealed no longitudinal effects, whereas OMth-w showed reduced variability in pwMS after treatment, alongside decreased depressive symptoms (p < 0.001). These findings highlight the value of variability-based approaches as a complementary framework to conventional GLM analyses for detecting treatment-related neuroplasticity in neurological populations.