Impaired P3 encoding and frontoparietal network imbalance characterize visual working memory deficits in newly diagnosed patients with multiple sclerosis: multimodal evidence from electrophysiology and structural neuroimaging

Working memory (WM) impairments affect a subset of multiple sclerosis (MS) patients even during early disease stages, yet the specific cognitive subprocesses and neural mechanisms underlying these deficits remain unclear. Using a multimodal neuroimaging approach combining high-density event-related potentials and structural MRI, we examined the temporal dynamics and structural correlates of WM dysfunction in recently diagnosed MS patients with less than six years of disease duration and minimal clinical disability. Thirty-four MS patients and 19 age-matched healthy controls performed a visuo-verbal WM task during high-density EEG recording and received complete neuropsychological and structural brain imaging evaluation. Behavioral analysis revealed significant WM impairment in a subgroup of MS patients. Electrophysiological findings showed markedly reduced P3 amplitudes during the encoding phase in impaired MS patients, suggesting weaker memory trace formation. Source localization analysis demonstrated aberrant frontoparietal activation patterns, with enhanced frontal engagement and attenuated posterior cortical activity in MS patients showing WM deficits. Structural neuroimaging revealed significant thalamic volume loss and cortical thinning in the right superior parietal and lingual gyri in memory impaired MS patients, regions central to visuospatial processing. Critically, gray matter alterations correlated significantly with electrophysiological markers and behavioral WM performance. These findings establish that early WM impairment in MS reflects disrupted encoding processes through abnormal frontoparietal network dynamics and selective structural degenerative changes. This integrated analysis clarifies the mechanistic basis of cognitive dysfunction in early MS and identifies neurobiological substrates amenable to targeted cognitive rehabilitation, with implications for early detection and intervention strategies to prevent accelerated cognitive decline.