Advancing Precision in Cognitive Rehabilitation in Multiple Sclerosis: Protocol for a Two-arm, Parallel-Group, Single Blind Assessor, Randomised by Stratification Controlled Trial Investigating Computerised Cognitive Training Effects on Cortical Organisation, Cognition and Daily Function (MS-NEUROPLAST)

Background Multiple sclerosis (MS) is a chronic autoimmune disease characterised by central nervous system inflammation, demyelination, and neurodegeneration, making it a leading cause of neurological disability in young and middle-aged adults. Symptoms vary widely, including motor dysfunction, fatigue, psychological issues, and cognitive decline, all significantly impacting the quality of life of people with MS (PwMS). Cognitive deficits, affecting up to 65% of PwMS, impair attention, memory, and executive functions, often worsening over time, particularly in progressive forms of the disease. Cognitive changes may be among the earliest signs of MS activity, yet current clinical tools lack the sensitivity for timely detection, delaying potential interventions. The clinical-radiological paradox—where imaging findings do not align well with patient symptoms—further challenges diagnosis and prognosis. Despite the high prevalence of cognitive impairment, a limited understanding of its mechanisms has slowed treatment development. However, cognitive rehabilitation, particularly computerised cognitive training (CCT), shows promise by promoting neuroplasticity and recovery. Real-world assessments are needed to detect subtle cognitive changes early and improve treatment strategies. Methods The MS-NEUROPLAST study is a randomised controlled trial with stratified randomisation that integrates electroencephalography (EEG) recordings, neuropsychological and physical assessments, patient-reported outcomes (PROMs), and daily activity monitoring. The 12-week CCT intervention uses the BrainHQ brain-training program. Measurements are taken at baseline and post-intervention. The study investigates the effects of CCT-induced neuroplasticity on cognitive outcomes and functional brain networks. The primary outcome is the effect of CCT on cortical functional organisation in PwMS, assessed via EEG. The secondary outcomes include CCT’s effects on cognition and PROMs in PwMS and baseline differences, including physical condition, from healthy controls. An exploratory outcome assesses whether daily activity features predict the primary and secondary outcomes. Discussion The MS-NEUROPLAST study adopts a multi-dimensional approach to cognitive rehabilitation in PwMS, aiming to capture the complexity of MS-related cognitive dysfunction and investigate how CCT can enhance cognitive function through neuroplasticity and cortical network reshaping. By integrating neurophysiological tools with real-world data from daily activities, this trial seeks to refine cognitive rehabilitation and develop more personalised, effective strategies to improve outcomes for PwMS. Trial Registration ClinicalTrials.gov NCT04806568