Along-Tract Microstructural Alterations Associated with Stimulant Misuse Localized using Diffusion MRI Tractometry

Diffusion brain MRI (dMRI) studies of substance use disorders have reported widespread but modest white matter (WM) microstructural alterations with limited anatomical specificity. Here, we applied segment-wise along-tract 3D tractometry to brain dMRI scans to localize fine-scale WM alterations associated with stimulant misuse using two complementary analytical frameworks: Bundle Analytics (BUAN) and Medial Tractography Analysis (MeTA). We analyzed 3D profiles of widely-used diffusion metrics across 33 major WM bundles in independent cohorts of cocaine (74 cases;58 controls) and amphetamine (22 cases;18 controls) users, testing the statistical associations with brain microstructure of pooled stimulant effects, substance-specific effects, and direct comparisons between stimulant classes. Segment-wise analyses revealed focal differences localized to specific tract segments rather than uniform differences along entire bundles. In pooled stimulant misuse, convergent findings across analysis pipelines were localized to hippocampal pathways and were consistent with altered microstructural organization. Amphetamines misuse showed a broader pattern of segment-wise differences across commissural, projection, and association pathways, involving altered axonal organization. No robust segment-wise differences were detected for cocaine misuse or between stimulant classes. These results show that WM alterations are spatially localized and reproducible across tractometry frameworks, highlighting the value of along-tract 3D mapping for improving anatomical specificity in addiction neuroimaging.