Longitudinal Degeneration of Microstructural and Structural Connectivity Patterns Following Stroke

Background: Stroke causes neurological impairment through local plasticity mechanisms, such as synaptic sprouting, and large-scale network reorganization. Although poststroke Wallerian degeneration is well established, whether white matter (WM) tracts' remodel over time to support behavioral recovery remains controversial. We investigated whether longitudinal changes in WM microstructure and structural connectivity are coupled to poststroke behavior, and how structural connectivity reorganization relates to local disconnection microstructure. Methods: In this prospective cohort study (Washington University, St. Louis; 2016-2018), patients with first-time stroke underwent diffusion-weighted magnetic resonance imaging and behavioral assessments at 2 weeks and 3 months poststroke; healthy controls were assessed twice. Latent factorial analysis was applied to behavioral and microstructural data from diffusion tensor imaging and neurite orientation dispersion and density imaging. Primary measures were whole-brain structural connectivity gradient divergences computed from tractography, microstructural diffusion parameters extracted from both WM and cortical regions disconnected by the lesion, and behavioral factors. Linear mixed models (adjusted for sociodemographic values) assessed longitudinal changes, linear regression assessed brain-behavior associations, and machine learning algorithms assessed differences between healthy controls and stroke. Results: Seventy-nine patients (age, 60±12 years; 43% female; diffusion-weighted magnetic resonance imaging: 48 at 2 weeks and 26 at 3 months) and 33 age-matched healthy controls were included. At 2 weeks, patients with stroke exhibited diffuse whole-brain alterations in WM organization. These widespread changes were closely linked to microstructural abnormalities in WM pathways disconnected by the lesion. Notably, WM degeneration progressed between 2 weeks and 3 months poststroke. Whole-brain structural connectivity alterations were associated with cognitive deficits acutely but not at 3 months, whereas microstructural parameters in disconnected tracts were primarily related to motor impairment. Conclusions: In patients with predominantly mild-severity stroke, we observed widespread and progressive alterations in WM microstructure that persists beyond the lesion and continues to evolve over time. Although acute structural disconnection relates to behavioral deficits, chronic WM degeneration appears largely uncoupled from functional recovery.