Fiber-specific white matter alterations in Parkinson's disease patients with freezing of gait

Freezing of gait (FOG) is a gait disorder that usually occurs in advanced stages of Parkinson's disease (PD). Understanding the underlying mechanism of FOG is important for treatment and prevention. Previous studies have investigated white matter (WM) structure to explore the pathology of FOG. However, the pathology is still unclear, possibly due to the methodological limitation in identifying specific fiber tracts. This study aimed to investigate tract-specific WM structural changes in FOG patients and their relationships with clinical characteristics. We enrolled 19 PD patients with FOG (PD-FOG), 19 without FOG (PD-woFOG) and 21 controls. Fixelbased analysis is a novel framework to avoid the effect of crossing fibers, which provides the metrics to assess WM morphology. By combining a method for segmenting fibers, we identified abnormalities in the specific fiber tracts. Compared to PD-woFOG, PD-FOG showed significant increased fiber-bundle cross-section (FC) in the corpus callosum (CC), fornix (FX), inferior longitudinal fasciculus (ILF), striato-premotor (ST_PREM), superior thalamic radiation (STR), thalamo-premotor (T_PREM), increased fiber density and cross-section (FDC) in the STR, and decreased fiber density (FD) in the CC and ILF. Additionally, the ILF was correlated with motor, cognition and memory, the CC was correlated with anxiety, and the T_PREM was also correlated with cognition. In conclusion, in addition to impairments of WM found in PD-FOG, we found enhancements in WM, which may imply compensatory mechanisms. Furthermore, multiple fiber tracts were correlated with clinical characteristics, especially the ILF, validating the involvement of transmission circuits of multiple distinct information in mechanisms of FOG.