{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T20:19:42Z","timestamp":1784665182688,"version":"3.55.0"},"reference-count":73,"publisher":"American Medical Association (AMA)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"<jats:sec id=\"ab-zoi250211-4\"><jats:title>Importance<\/jats:title><jats:p>Multiple sclerosis (MS) is an immune-mediated neurological disorder that affects 2.4 million people worldwide, and up to 60% experience anxiety.<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi250211-5\"><jats:title>Objective<\/jats:title><jats:p>To investigate whether anxiety in MS is associated with white matter lesion burden in the uncinate fasciculus (UF).<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi250211-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This was a retrospective case-control study of participants aged 18 years or older diagnosed with MS by an MS specialist and identified from the electronic medical record at a single-center academic medical specialty MS clinic in Pennsylvania. Participants received research-quality 3-Tesla magnetic resonance neuroimaging as part of MS clinical care from January 6, 2010, to February 14, 2018. After excluding participants with poor image quality, participants were stratified into 3 groups naturally balanced in age and sex: (1) MS without anxiety, (2) MS with mild anxiety, and (3) MS with severe anxiety. Analyses were performed from June 1 to September 30, 2024.<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi250211-7\"><jats:title>Exposure<\/jats:title><jats:p>Anxiety diagnosis and anxiolytic medication.<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi250211-8\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>Main outcomes were whether patients with severe anxiety had greater lesion burden in the UF than those without anxiety and whether higher anxiety severity was associated with greater UF lesion burden. Generalized additive models were used, with the burden of lesions (eg, proportion of fascicle impacted) within the UF as the outcome measure and sex, spline of age, and total brain volume as covariates.<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi250211-9\"><jats:title>Results<\/jats:title><jats:p>Among 372 patients with MS (mean [SD] age, 47.7 [11.4] years; 296 [80%] female), after anxiety phenotype stratification, 99 (27%) had no anxiety (mean [SD] age, 49.4 [11.7] years; 74 [75%] female), 249 (67%) had mild anxiety (mean [SD] age, 47.1 [11.1] years; 203 [82%] female), and 24 (6%) had severe anxiety (mean [SD] age, 47.0 [12.2] years; 19 [79%] female). UF burden was higher in patients with severe anxiety compared with no anxiety (<jats:italic>T<\/jats:italic>\u2009=\u20092.01 [<jats:italic>P<\/jats:italic>\u2009=\u2009.047]; Cohen <jats:italic>f<\/jats:italic><jats:sup>2<\/jats:sup>, 0.19 [95% CI, 0.08-0.52]). Additionally, higher mean UF burden was associated with higher severity of anxiety (<jats:italic>T<\/jats:italic>\u2009=\u20092.09 [<jats:italic>P<\/jats:italic>\u2009=\u2009.04]; Cohen <jats:italic>f<\/jats:italic><jats:sup>2<\/jats:sup>, 0.10 [95% CI, 0.05-0.21]).<\/jats:p><\/jats:sec><jats:sec id=\"ab-zoi250211-10\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>In this case-control study of UF lesion burden and anxiety in MS, overall lesion burden in the UF was associated with the presence and severity of anxiety. Future studies linking white matter lesion burden in the UF with treatment prognosis are warranted.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.4751","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T15:00:41Z","timestamp":1744642841000},"page":"e254751","source":"Crossref","is-referenced-by-count":5,"title":["Uncinate Fasciculus Lesion Burden and Anxiety in Multiple Sclerosis"],"prefix":"10.1001","volume":"8","author":[{"given":"Erica B.","family":"Baller","sequence":"first","affiliation":[{"name":"Department of Psychiatry, University of Pennsylvania, Philadelphia"},{"name":"Penn Lifespan Informatics and Neuroimaging Center, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey C.","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University of Pennsylvania, Philadelphia"},{"name":"Penn Lifespan Informatics and Neuroimaging Center, Philadelphia, 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Psychiatry, University of Pennsylvania, Philadelphia"},{"name":"Penn Lifespan Informatics and Neuroimaging Center, Philadelphia, Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa Lynne","family":"Martin","sequence":"additional","affiliation":[{"name":"Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Bar-Or","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Pennsylvania, Philadelphia"},{"name":"Center for Neuroinflammation and Neurotherapeutics, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ameena","family":"Elahi","sequence":"additional","affiliation":[{"name":"Department of Information Services, University of Pennsylvania, 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University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell T.","family":"Shinohara","sequence":"additional","affiliation":[{"name":"Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia"},{"name":"Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"issue":"9648","key":"zoi250211r1","doi-asserted-by":"publisher","first-page":"1502","DOI":"10.1016\/S0140-6736(08)61620-7","article-title":"Multiple sclerosis.","volume":"372","author":"Compston","year":"2008","journal-title":"Lancet"},{"issue":"2","key":"zoi250211r2","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1056\/NEJMra1401483","article-title":"Multiple 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