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It has gained recent interest, especially for its positive clinical outcomes in neurodegenerative diseases such as multiple sclerosis (MS). However, its simultaneous (during tDCS) and cumulative effects (following repeated tDCS sessions) on the regional brain activity during rest need further investigation, especially in MS. This study aims to elucidate tDCS\u2019 underpinnings, alongside its therapeutic impact in MS patients, using concurrent tDCS-MRI methods. In total, 20 MS patients (age = 48 \u00b1 12 years; 8 males) and 28 healthy controls (HCs; age = 36 \u00b1 15 years; 12 males) were recruited. They participated in a tDCS-MRI session, during which resting-state functional MRI (rs-fMRI) was used to measure the levels of the fractional amplitude of low-frequency fluctuations (fALFFs), which is an index of regional neuronal activity, before and during left anodal dorsolateral prefrontal cortex (DLPFC) tDCS (2.0 mA for 15 min). MS patients were then asked to return for an identical tDCS-MRI visit (follow-up) after 20 identical at-home tDCS sessions. Simultaneous tDCS-induced changes in fALFF are seen across cortical and subcortical areas in both HC and MS patients, with some regions showing increased and others decreased brain activity. In HCs, fALFF increased in the right pre- and post-central gyrus whilst it decreased in subcortical regions. Conversely, MS patients initially displayed increases in more posterior cortical regions but decreases in the superior and temporal cortical regions. At follow-up, MS patients showed reversed patterns, emphasizing significant cumulative effects of tDCS treatment upon brain excitation. Such long-lasting changes are further supported by greater pre-tDCS fALFFs measured at follow-up compared to baseline, especially around the cuneus. The results were significant after correcting for multiple comparisons (p-FDR &lt; 0.05). Our study shows that tDCS has both simultaneous and cumulative effects on neuronal activity measured with rs-fMRI, especially involving major brain areas distant from the site of stimulation, and it is responsible for fatigue and cognitive and motor skills.<\/jats:p>","DOI":"10.3390\/bioengineering12060672","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T06:11:07Z","timestamp":1750313467000},"page":"672","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Resting-State Activity Changes Induced by tDCS in MS Patients and Healthy Controls: A Simultaneous tDCS rs-fMRI Study"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1559-7113","authenticated-orcid":false,"given":"Marco","family":"Muccio","sequence":"first","affiliation":[{"name":"Department of Radiology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6226-5627","authenticated-orcid":false,"given":"Giuseppina","family":"Pilloni","sequence":"additional","affiliation":[{"name":"Department of Neurology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2743-412X","authenticated-orcid":false,"given":"Lillian","family":"Walton Masters","sequence":"additional","affiliation":[{"name":"Department of Neurology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peidong","family":"He","sequence":"additional","affiliation":[{"name":"Department of Radiology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Krupp","sequence":"additional","affiliation":[{"name":"Department of Neurology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6778-8125","authenticated-orcid":false,"given":"Abhishek","family":"Datta","sequence":"additional","affiliation":[{"name":"Research and Development, Soterix Medical, Inc., Woodbridge, NJ 07095, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marom","family":"Bikson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, City College of New York, New York, NY 10031, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4429-9713","authenticated-orcid":false,"given":"Leigh","family":"Charvet","sequence":"additional","affiliation":[{"name":"Department of Neurology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2320-6031","authenticated-orcid":false,"given":"Yulin","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Radiology, NYU Grossman School of Medicine, New York, NY 10016, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.brs.2016.06.004","article-title":"Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016","volume":"9","author":"Bikson","year":"2016","journal-title":"Brain Stimul."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Dedoncker, J., Baeken, C., De Raedt, R., and Vanderhasselt, M.A. (2021). 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