Brain Network Changes Underlying Non-motor Symptoms in Amyotrophic Lateral Sclerosis: A Multimodal MRI Perspective

Abstract

Amyotrophic lateral sclerosis (ALS) has evolved in clinical understanding from an isolated motor neuron disease into a complex multisystem disorder. Current evidence firmly establishes cognitive deficits and behavioral dysfunctions as inherent, non-motor elements of ALS, factors that drastically alter clinical outcomes, life expectancy, and caregiver stress. In light of this growing recognition, multimodal magnetic resonance imaging (MRI) has emerged as a crucial tool for elucidating the multiscale neuropathology of these symptoms, capturing a trajectory from structural damage to functional reorganization. Current findings demonstrate that atrophy in frontotemporal and subcortical regions, coupled with microstructural degradation in the corpus callosum and limbic white matter tracts, underpins deficits in executive function, social cognition, and emotional regulation. Resting-state functional MRI further reveals extensive network reorganization (primarily involving the default mode, frontoparietal control, and ventral attention networks) that appears to evolve from early compensatory hyperconnectivity to late-stage decompensation. More recently, the integration of multimodal data with predictive modeling has advanced the field toward individualized patient stratification and the early detection of cognitive decline. Operating under the premise that non-motor symptoms in ALS are clinical manifestations of widespread brain network degeneration, this review synthesizes recent advances in multimodal MRI. We highlight the structural basis, functional mechanisms, and individual variability of these symptoms, and discuss the translational potential of neuroimaging biomarkers in clinical practice.