Quantitative magnetization transfer and g-ratio imaging of white matter myelin in early psychotic spectrum disorders

Myelin abnormalities in white matter have been implicated in the pathophysiology of psychotic spectrum disorders (PSD), which are characterized by brain dysconnectivity as a core feature. Among evidence from in vivo MRI studies, diffusion imaging findings have largely supported disrupted white matter integrity in PSD; however, they are not specific to myelin changes. Using a multimodal imaging approach, the current study aimed to further delineate myelin and microstructural changes in the white matter of a young PSD cohort. We utilized quantitative magnetization transfer (qMT) imaging combined with advanced diffusion imaging to estimate specific myelin-related biophysical properties in 51 young adult PSD patients compared with 38 age-matched healthy controls. The macromolecular proton fraction (MPF) obtained from qMT was used as a specific marker of myelin content. Additionally, MPF was employed along with diffusion metrics of axonal density (v_ic) and extra-cellular volume fraction to derive the g-ratio, a measure of relative myelin sheath thickness defined as the ratio of inner to outer axonal diameter. Compared to controls, we observed a widespread MPF reduction and localized g-ratio increase in patients, primarily those with a diagnosis of schizophrenia or depressive schizoaffective disorder. No between-group differences were noted in v_ic, suggesting similar axonal densities across groups. Correlation analysis revealed that lower MPF was significantly related to poorer working memory performance in PSD, while the HC group showed a positive association for working memory with both g-ratio and v_ic. The pattern of changes observed in our multimodal imaging markers suggests that PSD, depending on symptomatology, is characterized by specific alterations in white matter integrity and myelin-axonal geometry of major white matter tracts, which may impact working memory function. These findings provide a more detailed view of myelin-related white matter changes in early stages of PSD.