We conducted a multimodal connectomic analysis in ALS patients and matched controls, integrating cortical thickness–based structural covariance networks, diffusion MRI tractography, and resting-state and task-based functional MRI. Graph-theoretical metrics were derived, and cross-modal structure–function correspondence was quantified using ROI-wise correlation analyses.

ALS participants showed preserved global network topology but evidence of selective reorganization, particularly within motor and interhemispheric pathways. Cortical covariance networks exhibited minimal association with functional dynamics, whereas diffusion-derived white matter connectivity remained closely aligned with functional organization. This structure–function coupling was maintained or even enhanced during task performance, suggesting adaptive reconfiguration rather than uniform disconnection.

Structure–function coupling in ALS is not globally diminished but reorganized, with robust white matter–functional relationships coexisting alongside weak cortical covariance–functional associations. These findings refine the traditional disconnection model and highlight the utility of multimodal metrics for understanding disease mechanisms and developing biomarkers for progression and therapeutic response.