Diffusion tensor imaging (DTI) can provide unique contrast and insight into microstructural changes with age or disease of the hippocampus, although it is difficult to measure the hippocampus because of its comparatively small size, location, and shape. This has been markedly improved by the advent of a clinically feasible 1‐mm isotropic resolution 6‐min DTI protocol at 3 T of the hippocampus with limited brain coverage of 20 axial‐oblique slices aligned along its long axis. However, manual segmentation is too laborious for large population studies, and it cannot be automatically segmented directly on the diffusion images using traditional T1 or T2 image‐based methods because of the limited brain coverage and different contrast. An automatic method is proposed here that segments the hippocampus directly on high‐resolution diffusion images based on an extension of well‐known deep learning architectures like UNet and UNet++ by including additional dense residual connections. The method was trained on 100 healthy participants with previously performed manual segmentation on the 1‐mm DTI, then evaluated on typical healthy participants (n = 53), yielding an excellent voxel overlap with a Dice score of ~ 0.90 with manual segmentation; notably, this was comparable with the inter‐rater reliability of manually delineating the hippocampus on diffusion magnetic resonance imaging (MRI) (Dice score of 0.86). This method also generalized to a different DTI protocol with 36% fewer acquisitions. It was further validated by showing similar age trajectories of volumes, fractional anisotropy, and mean diffusivity from manual segmentations in one cohort (n = 153, age 5–74 years) with automatic segmentations from a second cohort without manual segmentations (n = 354, age 5–90 years). Automated high‐resolution diffusion MRI segmentation of the hippocampus will facilitate large cohort analyses and, in future research, needs to be evaluated on patient groups.
