Sexual dimorphism of midbrain catecholaminergic metabolism revealed by neuromelanin-sensitive MRI

Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) is used as a proxy biomarker of midbrain catecholaminergic metabolism and synthesis capacity, particularly within dopaminergic nuclei. 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 18-40 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 p < 0.001). In contrast, conventional CNR normalization detected no sex differences in any region (all adjusted p > 0.20). Moreover, sex differences in NM-MRI signal were observed within the crus cerebri itself (p < 0.001), 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.