A proposed hierarchical framework of brain compensation following lower limb amputation: A cross-sectional analysis of the DEFINE (Deficit of Inhibition as a Marker of Neuroplasticity) cohort

Objectives Limb amputation leads to profound alterations in sensorimotor and cognitive-affective function, prompting the need for adaptive neuroplasticity to preserve quality of life. However, the brain’s capacity for structural compensation, and the factors that constrain or support this process, remain poorly understood. This study aims to investigate the associations between regional brain volumes and functional, sensory, psychological, and lifestyle variables in individuals with lower limb amputation, and, on that basis, to advance a hypothesis-generating hierarchical framework of brain compensation to guide future research. Methods This cross-sectional analysis included 14 participants from the Deficit of Inhibition as a Marker of Neuroplasticity (DEFINE) cohort who underwent high-resolution structural magnetic resonance imaging and clinical assessments at baseline. Brain volumes were analyzed using an artificial intelligence-based morphometric platform (NeuroQuant®), Functional mobility, pain modulation, cognitive performance, psychological symptoms, and lifestyle risk factors were evaluated. Correlational analyses were performed to explore the relationship between these variables and brain volume across cortical and subcortical regions. Results Higher mobility was significantly associated with greater volume in the caudate and inferior frontal cortex. Reduced tactile sensitivity and weaker pain inhibition were associated with reduced volume in the primary motor cortex, ventral diencephalon, and brainstem. Pain catastrophizing and alcohol use were linked to reduced thalamic and orbitofrontal volume. Conversely, better cognitive performance was associated with preserved entorhinal and cingulate cortex volumes. Notably, smoking and body mass index were linked to widespread volume reductions across sensorimotor and pain-modulatory regions. Conclusion Our findings suggest that factors such as age, lifestyle, and psychological burden may be relevant to brain adaptation after amputation, and they support the need for further longitudinal studies to clarify these relationships.