Task-induced 1/f slope modulation as a paradigm-independent marker of cognitive control in multiple sclerosis.

Multiple sclerosis (MS) is a chronic neuro-degenerative and inflammatory disease causing motor, sensory, and cognitive deficits, including impairments in working memory and attention. These cognitive deficits may arise from an imbalance between excitatory and inhibitory neural activity due to synaptic loss. Recent studies suggest that the aperiodic 1/f slope, a neural marker reflecting excitation/inhibition (E/I) balance, could serve as a biomarker for cognitive control. This study examines 1/f slope modulation during cognitive tasks in people with MS and healthy controls to investigate its potential as a paradigm-independent marker of cognitive control. We analyzed the Magnetoencephalography (MEG) data collected from 126 participants: 44 healthy controls (HCs), 61 people with MS not treated with benzodiazepines (pwMS(BZDn)), and 21 pwMS treated with benzodiazepines (pwMS(BZDp)). Participants performed an auditory oddball task and a visual-verbal n-back working memory task. After preprocessing MEG data, we used the specparam (formerly FOOOF) algorithm to extract the aperiodic 1/f slope from power spectral densities across 42 cortical parcels. Through this analysis, we observed significant steepening in the 1/f slope following stimulus onset for all stimulus types, with non-standard stimuli (targets and distractors) producing more pronounced effect (i.e., steeper slopes following stimulus onset). Compared to HCs, people with MS treated with benzodiazepines showed attenuated slope steepening in response to distractor stimuli, consistent with benzodiazepine-related impairments in inhibitory control. Moreover, unlike HCs, pwMS exhibited less steepening of 1/f slope response to distractors versus targets, indicating deficient phasic inhibition. Finally, in both HCs and pwMS(BZDn), the 1/f slope modulation was positively correlated across the auditory oddball and n-back tasks, pointing to a consistent, paradigm-independent neural mechanism. Taken together, these findings demonstrate that the aperiodic 1/f slope is a sensitive, paradigm-independent marker of cognitive control and E/I balance. The attenuated slope steepening in response to distractors in pwMS highlights disruptions in inhibitory neural processes underlying their cognitive deficits. These findings underscore the value of aperiodic spectral measures to deepen our understanding of cognitive impairments in MS.