Brain structural and functional connectivity in Parkinson's disease with freezing of gait

Abstract

Objective: To use a multimodal approach to assess brain structural pathways and resting state (RS) functional connectivity abnormalities in patients with Parkinson's disease and freezing of gait (PD-FoG).

Methods: T1-weighted, diffusion tensor (DT) MRI and RS functional MRI (fMRI) were obtained from 22 PD-FoG patients and 35 controls on a 3.0 T MR scanner. Patients underwent clinical, motor, and neuropsychological evaluations. Gray matter (GM) volumes and white matter (WM) damage were assessed using voxel based morphometry and tract-based spatial statistics, respectively. The pedunculopontine tract (PPT) was studied using tractography. RS fMRI data were analyzed using a model free approach investigating the main sensorimotor and cognitive brain networks. Multiple regression models were performed to assess the relationships between structural, functional, and clinical/cognitive variables. Analysis of GM and WM structural abnormalities was replicated in an independent sample including 28 PD-FoG patients, 25 PD patients without FoG, and 30 healthy controls who performed MRI scans on a 1.5 T scanner.

Results: Compared with controls, no GM atrophy was found in PD-FoG cases. PD-FoG patients showed WM damage of the PPT, corpus callosum, corticospinal tract, cingulum, superior longitudinal fasciculus, and WM underneath the primary motor, premotor, prefrontal, orbitofrontal, and inferior parietal cortices, bilaterally. In PD-FoG, right PTT damage was associated with a greater disease severity. Analysis on the independent PD sample showed similar findings in PD-FoG patients relative to controls as well as WM damage of the genu and body of the corpus callosum and right parietal WM in PD-FoG relative to PD no-FoG patients. RS fMRI analysis showed that PD-FoG is associated with a decreased functional connectivity of the primary motor cortex and supplementary motor area bilaterally in the sensorimotor network, frontoparietal regions in the default mode network, and occipital cortex in the visual associative network.

Conclusions: This study suggests that FoG in PD can be the result of a poor structural and functional integration between motor and extramotor (cognitive) neural systems.

Keywords: Parkinson's disease; brain connectivity; diffusion tensor MRI; freezing of gait; resting state functional MRI.

Figure 1

Probability map of the pedunculopontine tract and seeds of the pedunculopontine nucleus (green) are overlaid on the sagittal, coronal and axial sections of the Montreal Neurological Institute standard brain in neurological convention (right is right). The colour scale indicates the degree of overlap among subjects.

Figure 2

Decreased fractional anisotropy (FA, red) and increased mean diffusivity (MD, blue) in: A) patients with Parkinson's disease and freezing of gait (PD‐FoG) compared with healthy controls; B) PD‐FoG patients from the independent sample compared with matched controls; C) PD patients without FoG (PD‐noFoG) from the independent sample compared with matched controls. Results are overlaid on the axial sections of the Montreal Neurological Institute standard brain in neurological convention (right is right), and displayed at P < 0.05 family‐wise error (FWE) corrected for multiple comparisons at the cluster level using the threshold‐free cluster enhancement option. The white matter skeleton is shown in green.

Figure 3

Reduced resting state functional connectivity in the investigated networks in patients with Parkinson's disease and freezing of gait compared with healthy controls. Results are overlaid on the axial sections of the Montreal Neurological Institute standard brain in neurological convention (right is right), and displayed at P < 0.05 family‐wise error (FWE) corrected for multiple comparisons. Coloured bar represents P values.

Figure 4

Increased axial (axD, pink) in Parkinson's disease patients with freezing of gait (PD‐FoG) compared with those without FoG (PD‐noFoG) from the independent sample. Results are overlaid on the sagittal and axial sections of the Montreal Neurological Institute standard brain in neurological convention (right is right), and displayed at P < 0.05 family‐wise error (FWE) corrected for multiple comparisons at the cluster level using the threshold‐free cluster enhancement option. The white matter skeleton is shown in green.

Figure 5

Relationship between clinical disability, as assessed using the Unified Parkinsons' Disease Rating Scale III (UPDRS III) and axial diffusivity (axD) of the pedunculopontine tract (PPT) in the two groups of Parkinson's disease patients with freezing of gait (A and B: 3.0 T sample; C: independent 1.5 T sample).