BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease characterized by balance and gait impairment, fatigue, anxiety, depression, and diminished quality of life. Transcranial direct current stimulation (tDCS) has emerged as an effective intervention for managing these symptoms. OBJECTIVE: This study aims to investigate the efficacy of remotely supervised tDCS (RS-tDCS) applied to the left dorsolateral prefrontal cortex, in conjunction with a telerehabilitation (TR) program, on motor (balance and gait), cognitive (executive functions), and participation outcomes (fatigue, anxiety, depression, and quality of life) in persons with MS (pwMS). METHODS: In this multicenter interventional randomized controlled trial, pwMS were randomly assigned to: TR with active tDCS (TR RS-AtDCS, n = 20) or TR with sham tDCS (TR RS-StDCS, n = 21). Two additional groups of historical controls were represented by comparable TR (TR, n = 35) or usual care (UC, n = 35). The TR RS-tDCS program comprised a 6 weeks of rehabilitation intervention delivered through a hybrid mix model TR, five sessions a week each lasting 45 min with additional 20 min of tDCS during the first week. RESULTS: The subjects underwent to TR treatments (TR
TR RS-AtDCS
TR RS-StDCS) exhibited post-treatment improvements compared to UC group in Mini-BESTest global score (p = 0.013, T0 vs T1 ̶ UC group: p = 0.429, TR groups: p <
0.001), anterior postural control (p = 0.028, T0 vs T1 ̶ UC group: p = 0.860, TR groups: p <
0.001), and dynamic walking (p = 0.010, T0 vs T1 ̶ UC group: p = 0.269, TR groups: p = 0.012). The TR RS-AtDCS group showed improvement in the 12-item MSWS (p = 0.006) and STAI-Y (p = 0.032) compared to UC, TR and TR RS-StDCS. CONCLUSIONS: This study underscores the benefits of TR in addressing motor challenges (balance and gait) among pwMS. The incorporation of RS-tDCS positively impacted on participants' perceived walking difficulties and reduced anxiety. The novelty of this study lies in its comprehensive evaluation of motor, quality of life, and emotional outcomes within home-based interventions. These findings highlight the potential of combined interventions to enhance well-being in pwMS.