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Briefly, the proposed method segments cortical gray matter (GM) to derive a T1-weighted intensity threshold, which is applied inside co-registered T2 lesion masks to segment black hole lesion voxels. It was optimized on a training set (\n                      <jats:italic>N<\/jats:italic>\n                      \u2009=\u200940, 57.5% female, mean age 31.4\u2009\u00b1\u20098.7 (standard deviation) years), and 274 patients formed the test set (61.3% female, age 31.8\u2009\u00b1\u20098.4 years). Performance was quantified by the Dice similarity coefficient (DSC) and the intraclass correlation coefficient (ICC) for absolute agreement with manual segmentations. Lesion-wise sensitivity and specificity were calculated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Optimization resulted in: (1) GM selection as minimally 0.8 total WM plus GM partial volume, masked by MNI cortex; (2) normalized mutual information-driven linear co-registration of T2 to GdT1 images, interpolating T2 lesion masks using trilinear interpolation and 0.6 threshold; (3) mean intensity inside GM mask used as upper intensity threshold. The optimized method had acceptable spatial accuracy (DSC: 0.39\u2009\u00b1\u20090.26) and good volumetric accuracy (ICC: 0.84, 95% CI [0.72, 0.90]. Lesion-wise sensitivity was 0.91\u2009\u00b1\u20090.19, and lesion-wise specificity was 0.62\u2009\u00b1\u20090.22.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The proposed method to semi-automatically segment black holes from post-gadolinium T1-weighted images shows acceptable performance. As a potential aid to radiologists, the method is not recommended to be used entirely without human intervention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Points<\/jats:title>\n                    <jats:p>\n                      <jats:bold>\n                        <jats:italic>Question<\/jats:italic>\n                      <\/jats:bold>\n                      <jats:italic>T1-hypointense \u201cblack hole\u201d lesions reflect disease severity in multiple sclerosis but are not routinely quantified due to a lack of reliable analysis methods.<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:bold>\n                        <jats:italic>Findings<\/jats:italic>\n                      <\/jats:bold>\n                      <jats:italic>A rule-based semi-automated method for GdT1 \u201cblack hole\u201d lesion segmentation was developed and optimized, and then validated in a large unseen multi-center test set.<\/jats:italic>\n                    <\/jats:p>\n                    <jats:p>\n                      <jats:bold>\n                        <jats:italic>Clinical relevance<\/jats:italic>\n                      <\/jats:bold>\n                      <jats:italic>This method adds quantitative information about GdT1 \u201cblack hole\u201d lesions to the radiological assessment of multiple sclerosis disease severity, when false positives are manually removed. This can enhance the characterization of individual patients and advance the understanding of the disease.<\/jats:italic>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00330-026-12577-6","type":"journal-article","created":{"date-parts":[[2026,5,2]],"date-time":"2026-05-02T16:19:26Z","timestamp":1777738766000},"page":"7242-7255","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rule-based semi-automated method to segment black hole multiple sclerosis lesions on post-gadolinium 2D T1-weighted brain images"],"prefix":"10.1007","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5876-4260","authenticated-orcid":false,"given":"Rozemarijn M.","family":"Mattiesing","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fleur A.","family":"Groeneveld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iman","family":"Brouwer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald A.","family":"van Schijndel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederik","family":"Barkhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk J. 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Hugo Vrenken of Amsterdam UMC.","order":1,"name":"Ethics","label":"Guarantor","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"R.M.M. has received research support from Merck. I.B. has received research support from Merck, Novartis, Teva, and the Dutch MS Research Foundation. F.B. is a steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI\/ACTC and Prothena; Consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, Combinostics; Research agreements with Merck, Biogen, GE Healthcare, Roche; Co-founder and shareholder of Queen Square Analytics LTD. H.V. has received research support from Merck, Novartis, Pfizer, and Teva, consulting fees from Merck, and speaker honoraria from Novartis; all funds were paid to his institution. F.A.G., R.A.v.S., and H.J.M.M.M. report no disclosures.","order":2,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"No complex statistical methods were necessary for this paper.","order":3,"name":"Ethics","label":"Statistics and biometry","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"Written informed consent was obtained from all subjects (patients) in this study.","order":4,"name":"Ethics","label":"Informed consent","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"Institutional Review Board approval was obtained.","order":5,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"Some study subjects or cohorts have been previously reported in: Battaglini, M., Vrenken, H., Tappa Brocci, R., Gentile, G., Luchetti, L., Versteeg, A., Freedman, M. S., Uitdehaag, B. M. J., Kappos, L., Comi, G., Seitzinger, A., Jack, D., Sormani, M. P., Barkhof, F., & De Stefano, N. (2022); Evolution from a first clinical demyelinating event to multiple sclerosis in the REFLEX trial: Regional susceptibility in the conversion to multiple sclerosis at disease onset and its amenability to subcutaneous interferon beta-1a. European journal of neurology, 29(7), 2024\u20132035.\n                      \n                      ; Comi, G., De Stefano, N., Freedman, M. S., Barkhof, F., Uitdehaag, B. M. J., de Vos, M., Marhardt, K., Chen, L., Issard, D., & Kappos, L. (2017). Subcutaneous interferon \u03b2-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study. Journal of neurology, neurosurgery, and psychiatry, 88(4), 285\u2013294.\n                      \n                      ; De Stefano, N., Comi, G., Kappos, L., Freedman, M. S., Polman, C. H., Uitdehaag, B. M. J., Hennessy, B., Casset-Semanaz, F., Lehr, L., Stubinski, B., Jack, D. L., & Barkhof, F. (2014). Efficacy of subcutaneous interferon \u03b2-1a on MRI outcomes in a randomized controlled trial of patients with clinically isolated syndromes. Journal of neurology, neurosurgery, and psychiatry, 85(6), 647\u2013653.\n                      \n                      ; Gentile, G., Mattiesing, R. M., Brouwer, I., van Schijndel, R. A., Uitdehaag, B. M. J., Twisk, J. W. R., Kappos, L., Freedman, M. S., Comi, G., Jack, D., Barkhof, F., De Stefano, N., Vrenken, H., & Battaglini, M. (2023). The spatio-temporal relationship between concurrent lesion and brain atrophy changes in early multiple sclerosis: A post-hoc analysis of the REFLEXION study. NeuroImage. Clinical, 38, 103397.\n                      \n                      ; Mattiesing, R. M., Gentile, G., Brouwer, I., van Schijndel, R. A., Uitdehaag, B. M. J., Twisk, J. W. R., Kappos, L., Freedman, M. S., Comi, G., Jack, D., De Stefano, N., Barkhof, F., Battaglini, M., & Vrenken, H. (2022). The spatio-temporal relationship between white matter lesion volume changes and brain atrophy in clinically isolated syndrome and early multiple sclerosis. NeuroImage. Clinical, 36, 103220.\n                      \n                      ; Vrenken, H., Battaglini, M., de Vos, M. L., Nagtegaal, G. J., Teixeira, B. C. A., Seitzinger, A., Jack, D., Sormani, M. P., Uitdehaag, B. M. J., Versteeg, A., Comi, G., Kappos, L., De Stefano, N., & Barkhof, F. (2023). Temporal evolution of new T1-weighted hypo-intense lesions and central brain atrophy in patients with a first clinical demyelinating event treated with subcutaneous interferon \u03b2-1a. Journal of Neurology, 270(4), 2271\u20132282.\n                      \n                      ; Mattiesing, R. M., Kramer, E., Strijbis, E. M., Brouwer, I., van Schijndel, R. A., Gentile, G., Battaglini, M., De Stefano, N., Uitdehaag, B. M. J., Barkhof, F., Vrenken, H., & Schoonheim, M. M. (2024). Disease progression in the first 5 years of treatment in multiple sclerosis: Predictive value of early brain and lesion volume changes. Multiple Sclerosis Journal, 30(1), 44\u201354.\n                      \n                      ; Mattiesing, R. M., Stel, S., Mangroe, A. S., Brouwer, I., Versteeg, A., van Schijndel, R. A., Uitdehaag, B. M. J., Barkhof, F., Vrenken, H., & Kuijer, J. P. A. (2024). Validation of a semi-automated method to quantify lesion volume changes in multiple sclerosis on 2D proton-density-weighted scans based on image subtraction. Neuroimage: Reports, 4(1), 100194.","order":6,"name":"Ethics","label":"Study subjects or cohorts overlap","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"order":7,"name":"Ethics","label":"Methodology","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}}]}}