Diffusion MRI Metrics as Markers of Neuroinflammation in Mental Illness

Neuroinflammatory mechanisms are increasingly implicated in mental illness, but their characterization in the living human brain remains challenging. Diffusion magnetic resonance imaging (dMRI) is sensitive to tissue microstructure and offers a scalable approach for studying immune-related brain changes, yet it does not measure inflammation directly. Inflammatory processes alter the cellular and extracellular geometry that constrains water diffusion, and glial activation, edema, demyelination, and axonal injury may produce overlapping or opposing diffusion signatures. This review evaluates the extent to which commonly used and emerging dMRI metrics can support an inflammatory interpretation. It distinguishes signal representations, including diffusion tensor and kurtosis imaging, from biophysical models such as free-water imaging, neurite orientation dispersion and density imaging, diffusion basis spectrum imaging, and newer compartment models, and examines their mechanistic sensitivity and limitations. A review of studies combining dMRI with immune-related measures in psychiatric populations identified a heterogeneous literature dominated by small samples, peripheral biomarkers, and within-group associations. Free-water measures showed the most consistent associations with inflammatory markers, whereas tensor-derived findings were variable and large population studies indicated very small effect sizes. Evidence from compartment models, molecular imaging, and intervention studies remains sparse. Validation studies in experimental, histological, ex vivo, and cellular systems demonstrate that diffusion signals can reflect immune-related microstructural change but are not specific to inflammation. Future work should prioritize multimodal validation, mechanistically informed acquisition and modeling, and explicit testing of competing explanations. Once validated, dMRI could provide a scalable means of mapping immune-related microstructural change across the brain in mental illness.