Diffuse excessive high signal intensity in the preterm brain on advanced MRI represents widespread neuropathology

•Diffuse white matter abnormality appears at term in up to 80% of preterm infants.•Its potential pathology has been debated, with differing conclusions reached.•We use advanced diffusion models to delineate associated microstructural changes.•DWMA is associated with less branching and complexity of the corticospinal tract.•DWMA is associated with reduced neurite density throughout the white matter. Preterm brains commonly exhibit elevated signal intensity in the white matter on T2-weighted MRI at term-equivalent age. This signal, known as diffuse excessive high signal intensity (DEHSI) or diffuse white matter abnormality (DWMA) when quantitatively assessed, is associated with abnormal microstructure on diffusion tensor imaging. However, postmortem data are largely lacking and difficult to obtain, and the pathological significance of DEHSI remains in question. In a cohort of 202 infants born preterm at ≤32 weeks gestational age, we leveraged two newer diffusion MRI models – Constrained Spherical Deconvolution (CSD) and neurite orientation dispersion and density index (NODDI) – to better characterize the macro and microstructural properties of DWMA and inform the ongoing debate around the clinical significance of DWMA. With increasing DWMA volume, fiber density broadly decreased throughout the white matter and fiber cross-section decreased in the major sensorimotor tracts. Neurite orientation dispersion decreased in the centrum semiovale, corona radiata, and temporal lobe. These findings provide insight into DWMA's biological underpinnings and demonstrate that it is a serious pathology.