Abstract
Freezing of gait (FOG) has devastating consequences for patients with Parkinson's disease (PD), but the underlying pathophysiological mechanism is unclear. This was investigated in the present study by integrated structural and functional connectivity analyses of PD patients with or without FOG (PD FOG+ and PD FOG–, respectively) and healthy control (HC) subjects. We performed resting-state functional magnetic resonance imaging (fMRI) and diffusion tensor imaging of 24 PD FOG+ patients, 37 PD FOG– patients, and 24 HCs. Tract-based spatial statistics was applied to identify white matter (WM) abnormalities across the whole brain. Fractional anisotropy (FA) and mean diffusivity (MD) of abnormal WM areas were compared among groups, and correlations between these parameters and clinical severity as determined by FOG Questionnaire (FOGQ) score were analyzed. Voxel-mirrored homotopic connectivity (VMHC) was calculated to identify brain regions with abnormal interhemispheric connectivity. Structural and functional measures were integrated by calculating correlations between VMHC and FOGQ score and between FA, MD, and VMHC. The results showed that PD FOG+ and PD FOG– patients had decreased FA in the corpus callosum (CC), cingulum (hippocampus), and superior longitudinal fasciculus and increased MD in the CC, internal capsule, corona radiata, superior longitudinal fasciculus, and thalamus. PD FOG+ patients had more WM abnormalities than PD FOG– patients. FA and MD differed significantly among the splenium, body, and genu of the CC in all three groups (P < 0.05). The decreased FA in the CC was positively correlated with FOGQ score. PD FOG+ patients showed decreased VMHC in the post-central gyrus (PCG), pre-central gyrus, and parietal inferior margin. In PD FOG+ patients, VMHC in the PCG was negatively correlated with FOGQ score but positively correlated with FA in CC. Thus, FOG is associated with impaired interhemispheric brain connectivity measured by FA, MD, and VMHC, which are related to clinical FOG severity. These results demonstrate that integrating structural and functional MRI data can provide new insight into the pathophysiological mechanism of FOG in PD.
Highlights
Freezing of gait (FOG), which is among the most serious symptoms of Parkinson’s disease (PD) [1], is defined as the inability to achieve an effective gait when walking [2]
FOG Questionnaire (FOGQ), Frontal Assessment Battery (FAB), and Timed Up and Go (TUG) scores differed between PD FOG+ and PD FOG– patients (P < 0.001), but there were no differences in Mini-mental State Examination (MMSE) (P = 0.46), Montreal Cognitive Assessment (MoCA) (P = 0.353), Hamilton Depression Rating Scale (HDRS) (P = 0.34), or Hamilton Anxiety Rating Scale (HARS) (P = 0.76) scores between the two groups
The same trends were observed in the PD FOG– group—i.e., Fractional anisotropy (FA) was lower and mean diffusivity (MD) was higher in the corpus callosum (CC) and corona radiata compared to healthy control (HC) (Figure 2B)
Summary
Freezing of gait (FOG), which is among the most serious symptoms of Parkinson’s disease (PD) [1], is defined as the inability to achieve an effective gait when walking [2]. PD with FOG (PD FOG+) is characterized by severe and sudden gait disorder, with patients describing a feeling that their feet are glued to the floor. One explanation that has been proposed is that the difficulty of performing movements autonomously results in an increased reliance on attention to execute movements [5]. It has been suggested that executive dysfunction prevents PD patients from performing an action when it is required [6]. Bilateral coordination, and gait asymmetry are important aspects of freezing [7]
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