Research Article: Connectivity in ALS II (CoALS II): a study of structural and functional connectivity in ALS

Abstract:
Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a network-level neurodegenerative disease involving distributed disruptions across structural and functional systems. While previous studies have often examined white matter integrity or functional connectivity in isolation, the nature of structure–function coupling and its reorganization in ALS remains poorly understood. 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. A comprehensive 104-node parcellation scheme based on the Desikan-Killiany atlas was employed. ALS participants showed preserved global network topology ( p > 0.05 for efficiency and small-worldness) 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 ( p = 0.005), 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.

Introduction:
Amyotrophic lateral sclerosis (ALS) is increasingly recognized as a network-level neurodegenerative disease involving distributed disruptions across structural and functional systems. While previous studies have often examined white matter integrity or functional connectivity in isolation, the nature of structure–function coupling and its reorganization in ALS remains poorly understood.

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