Hidden Iron and Myelin Loss in Brain’s U-Fibers Marks Multiple Sclerosis Severity

Deep beneath the wrinkled surface of the human brain lies a network of short nerve fibers that neuroscientists have long suspected plays an outsized role in the disability caused by multiple sclerosis. These structures, known as U-fibers, arc just under the gray matter, connecting neighboring folds of the cortex like the stitching between adjacent pages of a book. A new study published in the Journal of Neurology now offers some of the most detailed evidence yet that these superficial white matter regions undergo measurable chemical changes in relapsing–remitting multiple sclerosis, and that those changes track closely with how disabled patients actually become.

The research, led by Yan Xie and Shaolong Wu of Henan Provincial People’s Hospital and Tongji Hospital in China, together with colleagues including Yi Wang at Weill Cornell Medicine and Meiyun Wang as senior author, compared 119 patients with relapsing–remitting multiple sclerosis, 47 patients with neuromyelitis optica spectrum disorders, and 93 healthy controls. The choice of comparison group matters. Neuromyelitis optica spectrum disorder was once lumped together with multiple sclerosis as a variant of the same disease, but it is now understood to be a fundamentally different condition, driven by antibodies against a water channel protein called aquaporin-4 rather than by the immune-mediated destruction of myelin that characterizes multiple sclerosis. Contrasting the two diseases in the same imaging framework therefore provides a kind of natural experiment: if a signal appears in multiple sclerosis but not in neuromyelitis optica, it likely reflects processes specific to multiple sclerosis pathology.

The technical heart of the study is an advanced magnetic resonance imaging method called susceptibility separation imaging, sometimes referred to as chi-separation. Conventional MRI is superb at revealing lesions, the bright scars that dot the brains of people with multiple sclerosis, but it says little about the underlying chemistry. Quantitative susceptibility mapping, a technique refined over the past decade, goes further by converting subtle distortions in the magnetic field measured by the scanner into maps of magnetic susceptibility, a physical property tied to the concentration of substances such as iron and myelin. Iron, sequestered in ferritin and heme within cells, is strongly paramagnetic and pushes susceptibility in the positive direction, while myelin, with its lipid-rich sheaths, is diamagnetic and pulls susceptibility negative. The trouble is that ordinary susceptibility maps blend these contributions into a single number, making it impossible to say whether a change reflects iron, myelin, or both.

Susceptibility separation imaging tackles this ambiguity head-on. Reconstructed from standard three-dimensional multi-echo gradient echo acquisitions, the method mathematically decomposes the total susceptibility signal into a positive component, denoted chi-pos, and a negative component, chi-neg. Histological validation work by other groups has shown that the positive component corresponds predominantly to iron stores, whereas the negative component is dominated by myelin. In effect, the technique gives researchers two separate dials, one roughly tracking tissue iron and the other tracking myelin integrity, from data that can be collected on conventional clinical scanners in a single session. That combination of chemical specificity and clinical practicality is what makes the approach attractive for large patient studies.

To focus on the U-fibers, the team defined the region of interest as the white matter lying within four millimeters beneath the gray-white matter boundary, and then divided this thin ribbon into a set of subregions across the whole brain. From each subregion they extracted total susceptibility as well as the positive and negative components, and used general linear models to compare the three groups while partial correlation analyses probed links with clinical measures. The results were strikingly asymmetric. In the multiple sclerosis patients, the positive susceptibility component, the putative iron signal, was significantly decreased in multiple temporal and limbic U-fiber regions relative to healthy controls. The negative component, associated with myelin, was significantly increased across a far more widespread set of U-fiber subregions.

The direction of these changes is as informative as their presence. A decrease in the iron-related signal in superficial white matter fits with a growing body of work suggesting that multiple sclerosis involves not just iron accumulation in deep gray matter structures but actual iron loss in certain tissue compartments, possibly reflecting the death of iron-rich glial cells, efflux of iron from damaged tissue, or dilution as tissue shrinks. Meanwhile, an increase in the negative, myelin-related component across broad U-fiber territories is consistent with demyelination and the inflammatory remodeling of myelin sheaths, processes that alter the diamagnetic signature of the tissue even outside visible lesions. That the myelin signal was abnormal across so many regions underscores a point that neuropathologists have made for decades: the damage in multiple sclerosis extends well beyond the discrete scars that radiologists can see on standard scans.

Perhaps the most consequential finding, however, is what the researchers did not find. When they compared the neuromyelitis optica spectrum disorder patients with healthy controls, no U-fiber subregion showed a significant difference in any susceptibility metric. In other words, the iron and myelin chemistry of the superficial white matter appeared essentially preserved in this disease, despite the fact that patients with neuromyelitis optica can carry a substantial burden of brain lesions and neurological impairment. This dissociation strengthens the argument that the susceptibility changes seen in multiple sclerosis are not a generic consequence of having an inflammatory brain disease, but instead reflect disease-specific processes, most plausibly the primary demyelination that defines multiple sclerosis pathology.

The story acquires an important caveat when the two patient groups are compared directly with each other. After the researchers adjusted for potential confounding effects of disease severity and lesion burden, the significant differences in susceptibility metrics between the multiple sclerosis and neuromyelitis optica groups disappeared. This suggests that part of the apparent disease-specificity may be explained by the fact that the multiple sclerosis patients in this cohort had greater lesion loads or more advanced disease. The U-fiber changes, in this reading, scale with the overall amount of tissue injury rather than being uniquely programmed by multiple sclerosis biology. Disentangling whether superficial white matter chemistry is a cause, a consequence, or simply a barometer of lesion burden will require longitudinal studies that follow patients from the earliest stages of disease.

What the study does establish firmly is a link to clinical disability. Within the multiple sclerosis group, the negative susceptibility component in U-fiber subregions correlated significantly with scores on the Expanded Disability Status Scale, the standard clinical measure of neurological impairment, with the strongest association in the left superior frontal region. That region houses short association fibers serving frontal lobe networks involved in executive function and cognitive control, domains that are frequently impaired in multiple sclerosis even when physical disability seems modest. The finding dovetails with prior work showing that U-fiber diffusion and susceptibility abnormalities relate to cognitive deficits and neurodegeneration, and it raises the possibility that susceptibility metrics could serve as surrogate markers, bridging the persistent gap between what radiologists see on conventional scans and what patients actually experience.

The implications reach toward clinical practice. Because susceptibility separation imaging can be reconstructed from gradient echo data already acquired in routine protocols, it could in principle be added to existing MRI examinations without new scan time, offering clinicians a quantitative readout of iron and myelin status in tissue that conventional sequences render as unremarkable. Such markers could eventually help monitor disease progression, evaluate whether experimental remyelinating therapies are working, and distinguish multiple sclerosis from its mimics at earlier stages. For now, the study’s authors are careful to frame the metrics as suggestive surrogate markers rather than diagnostic tests, and the cross-sectional design leaves open the question of whether the U-fiber changes precede visible lesions or follow them. Still, the work adds a compelling piece to a rapidly growing picture in which the brain’s thinnest, most overlooked layer of wiring, the short fibers hugging the cortical surface, turns out to be a sensitive mirror of the disease process, and a potential window into the biology of disability in multiple sclerosis.

Subject of Research: Iron and myelin susceptibility changes in U-fiber white matter in relapsing–remitting multiple sclerosis versus neuromyelitis optica spectrum disorders

Article Title: Comparison of iron and myelin changes in U‑fiber regions of relapsing–remitting multiple sclerosis and neuromyelitis optica spectrum disorders

Article References: Xie, Y., Wu, S., Zhang, Y., Ju, C., Zhang, S., Wang, Y., Zhu, W., & Wang, M. (2026). Comparison of iron and myelin changes in U‑fiber regions of relapsing–remitting multiple sclerosis and neuromyelitis optica spectrum disorders. Journal of Neurology, 273(10), Article 596. https://doi.org/10.1007/s00415-026-14054-y

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14054-y

Keywords: multiple sclerosis, neuromyelitis optica spectrum disorder, U-fibers, susceptibility separation imaging, quantitative susceptibility mapping, iron, myelin, white matter, MRI, Expanded Disability Status Scale, demyelination, superficial white matter