Purpose

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders1, characterized by progressive deterioration of motor function as well as a non-motor symptom complex2,3. To date, resting-state functional MRI (rs-fMRI) has been used to study the underlying neuropathological mechanisms of PD, and have focused on the critical role of the basal ganglia in PD motor symptoms3,4,5. However, only a few studies have investigated the role of the cerebellum5,6, especially the cerebellar vermis. In this study, rs-fMRI was utilized to investigate the functional connectivity (FC) differenes of the whole brain in PD patients compared with health controls (HC). We further examined the association of FC of vermis with motor and cognitive functional assessments in PD patients.

Materials and Methods

A cohort of 33 de novo PD patients (20 males / 13 females; age range: 46~77) was extracted from the Parkinson’s Progression Markers Initiative (PPMI) archive at baseline visit. All PD patients were evaluated with the UPDRS III motor section and a comprehensive neuropsychological evaluation. All MRI scanning was performed on 3T Siemens scanners. The rs-fMRI data was acquired using a T2* weighted single shot EPI sequence with TR/TE: 2400/25 ms; resolution: 3.294x3.294x3.3 mm3. High resolution T1-MPRAGE images were acquired with TR/TE: 2300/2.98 ms; resolution 1x1x1 mm3. Imaging data of 29 age-matched health controls (HC) were extracted either from the PPMI archive (n = 11) or from an existing database of healthy controls from an ongoing study (n = 8). The rs-fMRI data were preprocessed using the CONN toolbox (ver15) (http://www.nitrc.org/projects/conn) including slice timing, realignment, normalization to the MNI template space, spatial smoothing with a 6mm FWHM Gaussian kernel, and temporally band-pass filtering from 0.008-0.1 Hz. Nuisance variables, including the six motion parameters and BOLD signals from WM and CSF, were regressed out to remove motion and non-neuronal contributions. Whole brain ROI-to-ROI FC analysis was performed on the 132 ROIs based on the FSL Harvard-Oxford and the AAL atlas. Pearson correlation between the averaged BOLD signal from paired ROIs was calculated. A two-sample 2-sided T-test was used to compare the FC differences between PD and HC groups with FDR-corrected p < 0.05 for multiple comparisons. Since significant connectivity changes were identified in the vermis, we obtained an FC map from vermis to the whole brain. The FC difference map with significant clusters was obtained by comparing the HC and PD groups with voxel-wise p < 0.008 and cluster-wise FDR p < 0.05 to adjust for multiple comparisons. For PD patients, the partial correlation between the averaged FC of each significant cluster and motor severity (UPDRS III) and verbal learning and memory (Hopkins Verbal Learning Test- Revised; HVLT-R) were assessed using SPSS (ver25) controlled for age, gender, and education level and FDR corrected at p < 0.05.

Results

Figure 1 shows the FC changes between HC and PD patients at the whole brain level between the 132x132 ROI pairs. Although significant FC changes were observed in the vermis, cerebellum, inferior occipital cortex (iLOC), anterior inferior temporal gyrus (aITG), thalamus, and hippocampus, we focused our attention on FC changes associated with vermis because of the role of cerebellum in dyskinesia, tremor, gait and other non-motor symptoms. We observed significant FC difference between vermis-9, bilateral iLOC and left aITG. Figure 2 illustrates the significant clusters in the FC difference map of vermis between the HC and PD patients. The PD patients showed increased FC of vermis in bilateral iLOC and left aITG. Figure 3 showed the association between the FC of vermis and UPDRSIII and HVLT-R for PD patients. The FC between the vermis and right iLOC were positively associated with increased motor severity (r = .385, p = .048). The FC between the vermis and left iTG were negatively associated with increased HVLT-total recall (r = -.370, p = 0.034), suggesting that higher FC was associated with verbal memory deficits.

Discussion and Conclusion

The cerebral vermis in general receives somatic sensory, visual and auditory input via ascending spinal pathways and has intimate connections with other parts of cerebellum, which in turn project to cerebral cortex and brain stem and thus modulate the motor, visual and auditory system via a descending pathway. Both the iLOC and aITG are associated with visual processing, visual stimuli processing, and memory. Our results suggest that the FC between the vermis, iLOC and iTG are altered in PD patients compared with HC, and that these FC changes are related to motor dysfunction and visual-related memory deficits. These results suggest that the cerebral vermis, visual cortex, and visual processing associated areas contribute to the development of symptoms in PD.

Acknowledgements

No acknowledgement found.

References

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