Background Body region of onset and functional disability are key components of disease heterogeneity in amyotrophic lateral sclerosis (ALS).

Objectives To evaluate patterns of grey matter pathology in the motor cortex and correlate focal structural changes with functional disability.

Methods We conducted a single-centre neuroimaging study of a cohort of 33 cognitively normal patients with amyotrophic lateral sclerosis (ALS) and 44 healthy controls. A voxel-wise generalised linear model was used to investigate the distribution of disease burden within the motor cortex in relation to clinical disability.

Results Patients with bulbar onset have bilateral focal atrophy in the bulbar segment of the motor homunculus compared with patients with limb onset who have focal cortical changes in the limb segment of their motor strip. Furthermore, the extent to which different body regions are affected in ALS corresponds to the extent of focal grey matter loss in the primary motor cortex. Cortical ALS pathology also extends beyond the motor cortex affecting frontal, occipital and temporal regions.

Conclusions Focal grey matter atrophy within the motor homunculus corresponds with functional disability in ALS. The findings support the existing concepts of cortical focality and motor phenotype heterogeneity in ALS.