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However, despite strong translational evidence for sexual dimorphism in dopaminergic systems, inconsistent sex differences in NM-MRI signal limit its interpretability as a non-invasive measure of catecholaminergic synthesis capacity. A source of variability may be the reliance on contrast-to-noise ratio (CNR) normalization, which presupposes NM-MRI signal stability within the reference region, canonically the crus cerebri. To address this limitation, the present study introduced a novel normalization framework combining a data-driven reference region with residual-based, rather than ratio-based, normalization. NM-MRI data were acquired in a transdiagnostic sample of 101 adults, aged 18\u201340 years, including individuals with elevated familial risk for bipolar disorder or major depressive disorder. Sex effects on NM-MRI signal were compared across the substantia nigra pars compacta (SNc), ventral tegmental area (VTA), and locus coeruleus (LC) using conventional crus cerebri-based CNR versus residual-based normalization. Residual-based normalization revealed higher NM-MRI signal in males compared with females across all catecholaminergic nuclei (SNc, VTA, LC; all adjusted\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). In contrast, conventional CNR normalization detected no sex differences in any region (all adjusted\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&gt;\u20090.20). Moreover, sex differences in NM-MRI signal were observed within the crus cerebri itself (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001), indicating that the canonical reference region is not biologically invariant. Sexual dimorphism in midbrain NM-MRI signal is revealed in vivo for the first time using a novel residual-based normalization framework. By reducing reference-region bias, this approach advances NM-MRI toward candidate biomarker deployment for assessing catecholaminergic dysfunction in psychiatric and neurological disorders.\n                  <\/jats:p>","DOI":"10.1038\/s41380-026-03841-8","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T12:17:25Z","timestamp":1787833045000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sexual dimorphism of midbrain catecholaminergic metabolism revealed by neuromelanin-sensitive MRI"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-8958-1330","authenticated-orcid":false,"given":"Robert","family":"Raeder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9286-0694","authenticated-orcid":false,"given":"Helmet T.","family":"Karim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3857-1226","authenticated-orcid":false,"given":"Michele","family":"Bertocci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yui","family":"Asaoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manan","family":"Arora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke T.","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genna","family":"Bebko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haris A.","family":"Aslam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Graur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Atkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osasumwen","family":"Benjamin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5557-6969","authenticated-orcid":false,"given":"Dominique","family":"DiDomenico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richelle","family":"Stiffler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5842-6782","authenticated-orcid":false,"given":"Deepak K.","family":"Sarpal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6460-0118","authenticated-orcid":false,"given":"Zachary","family":"Freyberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4958-1291","authenticated-orcid":false,"given":"Mary L.","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"3841_CR1","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/nrn.2016.57","volume":"17","author":"AA Grace","year":"2016","unstructured":"Grace AA. 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