White matter changes in reward circuits of amyotrophic lateral sclerosis: a fixel-based study of appetite loss

Non-motor symptoms such as appetite loss contribute to weight and fat mass reduction in people living with Amyotrophic Lateral Sclerosis (plwALS), both of which are strong prognostic factors in the disease. Consequently, understanding the neural mechanisms underlying appetite and other non-motor disturbances in ALS is of significant clinical concern. Previous studies highlight widespread grey and white matter involvement beyond the motor system, including hypothalamic volume loss and functional changes in reward-related regions. However, it remains unclear whether structural alterations in white matter tracts implicated in reward processing and behaviour contribute to the multisystem pathology of ALS.

In this case-control study, we employ fixel-based analysis to examine changes in fibre characteristics of non-motor and motor tracts and their associations with clinical, anthropometric, and appetite-related measures within plwALS. Thirty-two plwALS and 24 non-neurodegenerative disease (NND) controls underwent multiband diffusion and structural imaging. Fixel-based analysis was conducted using MRtrix3 to model fibre pathways. For group-level statistical contrasts, fixels were generated in a common template space. We considered case-control differences, appetite, metabolism, body composition, and clinical measures.

Results reveal reductions in fibre density and cross-section in the corticospinal/corticobulbar and cerebellothalamic tracts. Exploratory analyses identified fibre density cross-section reductions throughout the temporo-ponto-cerebellar tract, the medial forebrain bundle, and the uncinate fasciculus. Though no direct associations were observed between fibre characteristics and measures of appetite or metabolism, we found significant correlation between fibre cross-section of the corticospinal/corticobulbar tracts and fat-free mass in NND controls, but not in plwALS. Furthermore, disease severity was associated with reduced fibre cross-section in the corticospinal/corticobulbar tract, medial forebrain bundle, uncinate fasciculus, and the temporopontine tract.

These findings highlight white matter fibre alterations in both motor and non-motor circuits in ALS. Although direct associations with appetite and metabolism were not observed, the results provide evidence of structural degeneration within reward- and behaviour-related pathways. Taken together, these findings reinforce that ALS is not confined to motor pathways but represents a multisystem neurodegenerative disease with both motor and extra-motor network involvement, offering important insights for future research into disease mechanisms and therapeutic targets.