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Introduction: Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique with simultaneous (during stimulation) and cumulative effects (after repeated sessions) on blood flow and neuronal metabolism. These effects remain mostly unclear especially in multiple sclerosis (MS). This work aims to elucidate brain metabolic and hemodynamic underpinnings of tDCS and its potential therapeutic impact in MS patients using quantitative tDCS-MRI., Methods: MS participants (n = 20; age = 45.4 ± 12.3 years, 7 males) underwent 3 T MRI scans before and after 20 daily sessions of dorsolateral prefrontal cortex (DLFPC) tDCS (2.0 mA, left anodal) paired with adaptive cognitive training (aCT). During both visits, imaging measurements of cerebral blood flow (CBF), cerebral venous blood oxygenation (Yv) and calculated cerebral metabolic rate of oxygen (CMRO 2 ) were obtained at pre-tDCS, during-tDCS and post-tDCS., Results: At baseline, significant increase from pre- to during-tDCS was observed in CMRO 2 (7.6%; p  = 0.002), CBF (11.0%; p  < 0.0001) and Yv (1.9%; p  = 0.006). At follow up, we observed an increase in pre-tDCS CMRO 2 (140.59 ± 13.83 μmol/100 g/min) compared to baseline pre-tDCS levels (128.30 ± 14.00 μmol/100 g/min; p  = 0.006). Sustained elevations in CMRO 2 and CBF into post-tDCS were also observed (tDCS lingering effects). Cumulative tDCS effects were observed in the form of sustained elevations in CMRO 2 and CBF in pre-tDCS follow up, reaching the magnitudes measured at baseline during-tDCS., Discussion: TDCS induces an acute surge in metabolic activity persisting immediately after the stimulation is removed. Moreover, treatment composed of repeated tDCS-aCT paired sessions contributes to establishing long-lasting increases in neuronal activity., Competing Interests: Soterix Medical Inc. provided the tDCS equipment used for research use. The City University of New York holds patents on brain stimulation with MB as inventor. The City University of New York holds patents on brain stimulation with AD as inventor. AD is an employee of Soterix Medical Inc. AD has equity in Soterix Medical Inc. MB has equity in Soterix Medical Inc. MB consults, received grants, assigned inventions, and/or serves on the SAB of SafeToddles, Boston Scientific, GlaxoSmithKline, Biovisics, Mecta, Lumenis, Halo Neuroscience, Google-X, i-Lumen, Humm, Allergan (Abbvie), Apple. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Muccio, Pilloni, Walton Masters, He, Krupp, Datta, Bikson, Charvet and Ge.)