{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T14:44:08Z","timestamp":1784731448448,"version":"3.55.0"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T00:00:00Z","timestamp":1626220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000890","name":"National Multiple Sclerosis Society","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000890","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001804","name":"Canada Research Chairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p><jats:bold>Introduction:<\/jats:bold> The source of Tissue Sodium Concentration (TSC) increase in Multiple Sclerosis (MS) remains unclear, and could be attributed to altered intracellular sodium concentration or tissue microstructure. This paper investigates sodium in MS using three new MRI sequences.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> Three sodium scans were acquired at 4.7 T from 30 patients (11 relapsing-remitting, 10 secondary-progressive, 9 primary-progressive) and 9 healthy controls including: Density-Weighted (NaDW), with very short 30\u00b0 excitation for more accurate TSC measurement; Projection Acquisition with Coherent MAgNetization (NaPACMAN), designed for enhanced relaxation-based contrast; and Soft Inversion Recovery FLuid Attenuation (NaSIRFLA), developed to reduce fluid space contribution. Signal was measured in both lesions (<jats:italic>n<\/jats:italic> = 397) and normal appearing white matter (NAWM) relative to controls in the splenium of corpus callosum and the anterior and posterior limbs of internal capsule. Correlations with clinical and cognitive evaluations were tested over all MS patients.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> Sodium intensity in MS lesions was elevated over control WM by a greater amount for NaPACMAN (75%) than NaDW (35%), the latter representing TSC. In contrast, NaSIRFLA exhibited lower intensity, but only for region specific analysis in the SCC (\u22127%). Sodium intensity in average MS NAWM was not significantly different than control WM for either of the three scans. NaSIRFLA in the average NAWM and specifically the posterior limb of internal capsules positively correlated with the Paced Auditory Serial Addition Test (PASAT).<\/jats:p><jats:p><jats:bold>Discussion:<\/jats:bold> Lower NaSIRFLA signal in lesions and ~2\u00d7 greater NaPACMAN signal elevation over control WM than NaDW can be explained with a demyelination model that also includes edema. A NAWM demyelination model that includes tissue atrophy suggests no signal change for NaSIRFLA, and only slightly greater NAWM signal than control WM for both NaDW and NaPACMAN, reflecting experimental results. Models were derived from previous total and myelin water fraction study in MS with T2-relaxometry, and for the first time include sodium within the myelin water space. Reduced auditory processing association with lower signal on NaSIRFLA cannot be explained by greater demyelination and its modeled impact on the three sodium MRI sequences. Alternative explanations include intra- or extracellular sodium concentration change. Relaxation-weighted sodium MRI in combination with sodium-density MRI may help elucidate microstructural and metabolic changes in MS.<\/jats:p>","DOI":"10.3389\/fneur.2021.693447","type":"journal-article","created":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T21:16:26Z","timestamp":1626297386000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Sodium Intensity Changes Differ Between Relaxation- and Density-Weighted MRI in Multiple Sclerosis"],"prefix":"10.3389","volume":"12","author":[{"given":"Robert","family":"Stobbe","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Boyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Penelope","family":"Smyth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Emery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Vald\u00e9s Cabrera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Beaulieu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1093\/brain\/awp334","article-title":"Brain tissue sodium concentration in multiple sclerosis: a sodium imaging study at 3 Tesla","volume":"133","author":"Inglese","year":"2010","journal-title":"Brain."},{"key":"B2","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1148\/radiol.12112680","article-title":"Distribution of brain sodium accumulation correlates with disability in multiple sclerosis: a cross-sectional Na-23 MR imaging study","volume":"264","author":"Zaaraoui","year":"2012","journal-title":"Radiology."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1136\/jnnp-2013-306573.29","article-title":"Sodium accumulation is associated with disability and progression in multiple sclerosis: a Na-23 MRI Study","volume":"84","author":"Paling","year":"2013","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"B4","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s10334-013-0396-1","article-title":"Topography of brain sodium accumulation in progressive multiple sclerosis","volume":"27","author":"Maarouf","year":"2014","journal-title":"Magn Reson Mat Phys Biol Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1177\/1352458515609430","article-title":"Heterogeneity of acute multiple sclerosis lesions on sodium (Na-23) MRI","volume":"22","author":"Eisele","year":"2016","journal-title":"Mult Scler J."},{"key":"B6","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.msard.2019.01.027","article-title":"Temporal evolution of acute multiple sclerosis lesions on serial sodium (Na-23) MRI","volume":"29","author":"Eisele","year":"2019","journal-title":"Mult Scler Relat Disord."},{"key":"B7","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1111\/jon.12448","article-title":"Sodium MRI of T1 high signal intensity in the dentate nucleus due to gadolinium deposition in multiple sclerosis","volume":"27","author":"Eisele","year":"2017","journal-title":"J Neuroimag."},{"key":"B8","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1212\/WNL.0000000000003511","article-title":"Increased total sodium concentration in gray matter better explains cognition than atrophy in MS","volume":"88","author":"Maarouf","year":"2017","journal-title":"Neurology."},{"key":"B9","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.jns.2017.06.003","article-title":"Na-23 MRI reveals persistent sodium accumulation in tumefactive MS lesions","volume":"379","author":"Huhn","year":"2017","journal-title":"J Neurol Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1177\/1352458517736146","article-title":"Metabolic counterparts of sodium accumulation in multiple sclerosis: a whole brain Na-23-MRI and fast H-1-MRSI study","volume":"25","author":"Donadieu","year":"2019","journal-title":"Mult Scler J."},{"key":"B11","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1136\/jnnp-2018-319634","article-title":"Cortical grey matter sodium accumulation is associated with disability and secondary progressive disease course in relapse-onset multiple sclerosis","volume":"90","author":"Brownlee","year":"2019","journal-title":"J Neurol Neurosurg Psychiatry."},{"key":"B12","doi-asserted-by":"publisher","first-page":"84","DOI":"10.3389\/fneur.2019.00084","article-title":"Potential of sodium MRI as a biomarker for neurodegeneration and neuroinflammation in multiple sclerosis","volume":"10","author":"Huhn","year":"2019","journal-title":"Front Neurol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1002\/nbm.3312","article-title":"Quantitative sodium MRI of the human brain at 9.4T provides assessment of tissue sodium concentration and cell volume fraction during normal aging","volume":"29","author":"Thulborn","year":"2016","journal-title":"NMR Biomedicine."},{"key":"B14","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1038\/nrn2023","article-title":"Axonal conduction and injury in multiple sclerosis: the role of sodium channels","volume":"7","author":"Waxman","year":"2006","journal-title":"Nat Rev Neurosci."},{"key":"B15","doi-asserted-by":"publisher","first-page":"31269","DOI":"10.1038\/srep31269","article-title":"Sodium MRI in multiple sclerosis is compatible with intracellular sodium accumulation and inflammation-induced hyper-cellularity of acute brain lesions","volume":"6","author":"Biller","year":"2016","journal-title":"Sci Rep."},{"key":"B16","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1093\/brain\/awv386","article-title":"Brain intra- and extracellular sodium concentration in multiple sclerosis: a 7 T MRI study","volume":"139","author":"Petracca","year":"2016","journal-title":"Brain."},{"key":"B17","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1002\/nbm.3376","article-title":"Residual quadrupole interaction in brain and its effect on quantitative sodium imaging","volume":"29","author":"Stobbe","year":"2016","journal-title":"NMR Biomedicine."},{"key":"B18","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1002\/mrm.20696","article-title":"In vivo sodium magnetic resonance imaging of the human brain using soft inversion recovery fluid attenuation","volume":"54","author":"Stobbe","year":"2005","journal-title":"Magn Reson Med."},{"key":"B19","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1002\/mrm.27738","article-title":"Sodium MRI revisited","volume":"82","author":"Burstein","year":"2019","journal-title":"Magn Reson Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s10334-013-0390-7","article-title":"Exploring and enhancing relaxation-based sodium MRI contrast","volume":"27","author":"Stobbe","year":"2014","journal-title":"Magn Reson Mat Phys Biol Med."},{"key":"B21","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1002\/ana.22366","article-title":"Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria","volume":"69","author":"Polman","year":"2011","journal-title":"Ann Neurol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e01514","DOI":"10.1002\/brb3.1514","article-title":"Diffusion tensor imaging tractography reveals altered fornix in all diagnostic subtypes of multiple sclerosis","volume":"10","author":"Valdes Cabrera","year":"2020","journal-title":"Brain Behav"},{"key":"B23","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.mri.2019.08.012","article-title":"23Na MRI of human skeletal muscle using long inversion recovery pulses","volume":"16","author":"Wilferth","year":"2019","journal-title":"Mag Reson Imaging."},{"key":"B24","doi-asserted-by":"publisher","first-page":"4763","DOI":"10.1038\/srep04763","article-title":"A method for estimating intracellular sodium concentration and extracellular volume fraction in brain in vivo using sodium magnetic resonance imaging","volume":"4","author":"Madelin","year":"2014","journal-title":"Sci Rep."},{"key":"B25","doi-asserted-by":"publisher","first-page":"2968","DOI":"10.1002\/mrm.26962","article-title":"Calculating potential error in sodium MRI with respect to the analysis of small objects","volume":"79","author":"Stobbe","year":"2018","journal-title":"Magn Reson Med."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1158\/1078-0432.CCR-18-2079","article-title":"Residual tumor volume, cell volume fraction, and tumor cell kill during fractionated chemoradiation therapy of human glioblastoma using quantitative sodium MR imaging","volume":"25","author":"Thulborn","year":"2019","journal-title":"Clin Cancer Res."},{"key":"B27","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1016\/j.nurt.2007.05.004","article-title":"Magnetic resonance imaging of myelin","volume":"4","author":"Laule","year":"2007","journal-title":"Neurotherapeutics."},{"key":"B28","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1016\/j.pnmrs.2014.02.001","article-title":"Sodium MRI: methods and applications","volume":"79","author":"Madelin","year":"2014","journal-title":"Nuclear Magn Reson Spectrosc"},{"key":"B29","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1007\/s00415-004-0306-6","article-title":"Water content and myelin water fraction in multiple sclerosis\u2014a T-2 relaxation study","volume":"251","author":"Laule","year":"2004","journal-title":"J Neurol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1277","DOI":"10.1152\/physrev.00027.2007","article-title":"Diffusion in brain extracellular space","volume":"88","author":"Sykova","year":"2008","journal-title":"Physiol Rev."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2133","DOI":"10.1016\/j.bpj.2017.06.052","article-title":"Brain extracellular space: the final frontier of neuroscience","volume":"113","author":"Nicholson","year":"2017","journal-title":"Biophys J."},{"key":"B32","doi-asserted-by":"publisher","first-page":"71","DOI":"10.3233\/BPL-160033","article-title":"Magnetic resonance of myelin water: an in vivo marker for myelin","volume":"2","author":"MacKay","year":"2016","journal-title":"Brain Plast"},{"key":"B33","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.acn.2005.07.006","article-title":"A comprehensive review of the paced auditory serial addition test (PASAT)","volume":"21","author":"Tombaugh","year":"2006","journal-title":"Arch Clin Neuropsychol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"366","DOI":"10.2215\/CJN.07400717","article-title":"Serum sodium and cognition in older community-dwelling men","volume":"13","author":"Nowak","year":"2018","journal-title":"Clin J Am Soc Nephrol"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.693447\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,16]],"date-time":"2021-07-16T14:46:47Z","timestamp":1626446807000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2021.693447\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,14]]},"references-count":34,"alternative-id":["10.3389\/fneur.2021.693447"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2021.693447","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,14]]},"article-number":"693447"}}