The human connectome holds considerable promise for advancing an integrated, systems-level understanding of brain disorders. Critical to this ambition is accurate, reliable, and biologically informative connectome mapping and analysis in the presence of diverse brain pathologies. However, many connectome-mapping methodologies have been established and validated using healthy, non-clinical participants. Here, we consider the challenges of structural connectome mapping in the presence of pathology. We first classify connectome abnormalities and relate them to underlying white-matter microstructure. We explain how measures of structural connectivity can quantify the impact of microstructural white-matter pathology on the macroscale connectome, including measures based on streamline counts, microstructure-informed tractography, tract-averaged metrics, and structural similarity. We consider connectome-mapping pipelines and algorithmic choices to facilitate reliable and biologically meaningful clinical connectome mapping. Our aim is to establish best practices for connectome mapping and analysis in neurology, psychiatry, and neurosurgery.
Zalesky et al. (2026) studied this question.