Introduction

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder. PD patients are usually classified as tremor-dominant (TD) and postural instability and gait disorder (PIGD) phenotypes, based on the predominant motor signs. Recent MRI studies demonstrated that different PD subgroups are characterized by diverse pathophysiology mechanisms. Along with the well-known striato-thalamo-cortical pathway, involvement of the cerebello-thalamo-cortical circuit (CTC) has been linked to motor symptoms development in PD. For example, several lines of evidence suggest the crucial involvement of the CTC in PD tremor. Our aim was to investigate functional alterations within motor circuits of the cerebro-cerebellar system in TD and PIGD PD subtypes using stepwise functional connectivity (SFC) method.

Methods

58 PD patients performed clinical and cognitive evaluations and resting state functional MRI. PD population was divided into two groups: 32 PD patients with TD (PD-TD) and 26 with PIGD (PD-PIGD). 60 age- and sex-matched controls were also enrolled. RS-fMRI data processing was performed with the Data Processing Assistant for Resting-State toolbox (DPARSFA). Association matrices for each participant were computed by calculating the Pearson correlation between each voxel time courses within a mask covering cortical and subcortical grey matter. The preprocessed resting state images of each participant were previously converted to an N-by-M matrix, where N was the image voxels in MNI space, and M was the 200 acquisition time points. From this step, a 11705x11705 matrix of Pearson correlation coefficients (r-values) was obtained for each individual. Fisher z transformation was applied to r-values. Then, all negative correlations and positive correlations that did not reach a false discovery rate (FDR) correction threshold of p<0.05 were excluded from further analyses. SFC analysis is a graph-theory-based method that detects functional couplings of a seed region to other regions in the brain. Particularly, SFC was used to characterize the pattern of functional connectivity between a cerebellar seed region and the rest of the brain at direct, short, intermediate, and long functional connectivity distances, thus covering the continuum from the cerebellum to the cortical hubs. The cerebellar seed-region was identified using motor task-based functional MRI in an independent group of 23 healthy controls. Then, a mask including the cerebellar seed region was obtained. Each step map encoded the number of step connections between every voxel in the brain and the voxels within the mask including seed region. For each of the SFC maps, whole-brain two-sample t-test comparisons between each group were performed, including age and gender as covariates. A threshold-free cluster enhancement method, combined with nonparametric permutation testing (5000 permutations) was used to detect statistically significant differences at p<0.05, family-wise error (FWE) corrected.

Results

In the healthy control, the performance of the motor task during functional MRI was associated with activation of the lobule VI (left and right) and vermis of the cerebellum. A cluster containing these regions was used as seed-cerebellar region. In the SFC analysis, significant differences were found between groups. At one-link step distance, in both PD subtypes, the seed region showed decreased regional–local functional connectivity with thalamus and parietal lobe (precuneus and inferior parietal gyrus) relative to healthy controls; across intermediate link-steps, a reduced connectivity was observed between the seed region and frontal, parietal and occipital lobes. Interestingly, only PD-PIGD patients showed lower connectivity at intermediate link-step distances between the seed-cerebellar region and sensorimotor areas (precentral and postcentral regions). By contrast, at the first link-step distance, PD-PIGD showed increased connectivity only between lobule VI of cerebellum and insula and inferior frontal gyrus compared to controls and PD-TD patients. These alterations are also confirmed at subsequent link-step distances, even with a small altered pattern. On the other hand, at the initial steps of cerebellar functional connectivity streams, PD-TD patients displayed a significant enhancements of connectivity degree with orbitofrontal cortex and inferior temporal gyrus relative to both controls and PD-PIGD patients. These alterations are also confirmed at subsequent link-step distances.

Discussion

Our results suggest that an atypical flow of information from short to long functional distances between cerebellum, thalamus and default-mode regions occurs in both PD clinical variants. The decreased connectivity findings between cerebellar seed regions and sensorimotor cortex observed only in PD-PIGD are in line with the suspected pathophysiology of PD gait disorders. In addition, SFC pattern identified different localization of functional over‐connectivity in frontal lobe in the two patient groups: within inferior frontal gyrus and insula in PD-PIGD, and in orbitofrontal gyrus in PD-TD. Hyperactivation of the frontal lobe might reflect in both PD subgroups a maladaptive compensatory response to cerebello-thalamo-cortical circuit dysfunction.

Conclusions

These findings highlight subtype-specific PD changes in cerebellar connectivity, providing novel insights into the pathophysiological mechanism potentially underlying different motor phenotypes.

Acknowledgements

Supported by: Ministry of Education and Science Republic of Serbia (Grant #175090).

References

No reference found.