Unsupervised segmentation, clustering, and groupwise registration of heterogeneous populations of brain MR images.

Population analysis of brain morphology from magnetic resonance images contributes to the study and understanding of neurological diseases. Such analysis typically involves segmentation of a large set of images and comparisons of these segmentations between relevant subgroups of images (e.g., "normal" versus "diseased"). The images of each subgroup are usually selected in advance in a supervised way based on clinical knowledge. Their segmentations are typically guided by one or more available atlases, assumed to be suitable for the images at hand. We present a data-driven probabilistic framework that simultaneously performs atlas-guided segmentation of a heterogeneous set of brain MR images and clusters the images in homogeneous subgroups, while constructing separate probabilistic atlases for each cluster to guide the segmentation. The main benefits of integrating segmentation, clustering and atlas construction in a single framework are that: 1) our method can handle images of a heterogeneous group of subjects and automatically identifies homogeneous subgroups in an unsupervised way with minimal prior knowledge, 2) the subgroups are formed by automatical detection of the relevant morphological features based on the segmentation, 3) the atlases used by our method are constructed from the images themselves and optimally adapted for guiding the segmentation of each subgroup, and 4) the probabilistic atlases represent the morphological pattern that is specific for each subgroup and expose the groupwise differences between different subgroups. We demonstrate the feasibility of the proposed framework and evaluate its performance with respect to image segmentation, clustering and atlas construction on simulated and real data sets including the publicly available BrainWeb and ADNI data. It is shown that combined segmentation and atlas construction leads to improved segmentation accuracy. Furthermore, it is demonstrated that the clusters generated by our unsupervised framework largely coincide with the clinically determined subgroups in case of disease-specific differences in brain morphology and that the differences between the cluster-specific atlases are in agreement with the expected disease-specific patterns, indicating that our method is capable of detecting the different modes in a population. Our method can thus be seen as a comprehensive image-driven population analysis framework that can contribute to the detection of novel subgroups and distinctive image features, potentially leading to new insights in the brain development and disease.