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Neurosurgical resection is one of the few opportunities researchers have to image the human brain pre‐ and postfocal damage. A major challenge associated with brains undergoing surgical resection is that they often do not fit brain templates most image‐processing methodologies are based on. Manual intervention is required to reconcile the pathology, requiring time investment and introducing reproducibility concerns, and extreme cases must be excluded.

We propose an automatic longitudinal pipeline based on High Angular Resolution Diffusion Imaging acquisitions to facilitate a Pathway Lesion Symptom Mapping analysis relating focal white matter injury to functional deficits. This two‐part approach includes (i) automatic segmentation of focal white matter injury from anisotropic power differences, and (ii) modeling disconnection using tractography on the single‐subject level, which specifically identifies the disconnections associated with focal white matter damage.

The advantages of this approach stem from (1) objective and automatic lesion segmentation and tractogram generation, (2) objective and precise segmentation of affected tissue likely to be associated with damage to long‐range white matter pathways (defined by anisotropic power), (3) good performance even in the cases of anatomical distortions by use of nonlinear tensor‐based registration, which aligns images using an approach sensitive to white matter microstructure.

Mapping a system as variable and complex as the human brain requires sample sizes much larger than the current technology can support. This pipeline can be used to execute large‐scale, sufficiently powered analyses by meeting the need for an automatic approach to objectively quantify white matter disconnection.