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Pathological changes in subcortex disrupt cortical synchronization and metastability affecting cognitive function in Parkinson’s disease

Cheng Zhou¹ and Minming Zhang¹
¹Zhejiang University, Hangzhou, China

Synopsis

In this paper, we investigated spatiotemporal dynamics of the phase interactions among resting-state blood oxygen level-dependent signals of Parkinson’s disease patients (n = 159) and normal controls (n = 152). We demonstrated that diminished dopaminergic function and the pathological changes in thalamus related structures responsible for decreased cortical synchronization and metastability, further affect cognitive function in Parkinson’s disease.

Abstract

Parkinson’s disease is primarily characterized by loss of dopaminergic cells and atrophy in subcortical regions. However, the impact of these changes on large-scale dynamic integration and segregation of cortex are not well understood. In this paper, we investigated spatiotemporal dynamics of the phase interactions among resting-state blood oxygen level-dependent signals of Parkinson’s disease patients (n = 159) and normal controls (n = 152). We found cortical synchronization and metastability in Parkinson’s disease patients are significantly decreased. To examine the causal role of dopamine depletion in cortical synchronization and metastability, we investigated 45 Parkinson’s disease patients, both at OFF (at least 12 hours after withholding dopaminergic drugs) and ON (one hour after administration of 200 mg L-dopa and 50 mg benserazide) state. We found that cortical synchronization and metastability in Parkinson’s disease patients are significantly increased in the ON state. Furthermore, the extent of cortical synchronization and metastability in the OFF state reflected cognitive performance and mediate the difference of cognitive performance between Parkinson’s disease patients and normal controls. In addition, we demonstrated that measures of both the thalamus total grey matter volume and subcortical-cortical structural connectivity had a positive relationship with cortical synchronization and metastability in the dopaminergic OFF state. No such relationships were found in normal controls. Mediation analysis showed that the difference of thalamus total grey matter volume and thalamocortical structural connectivity mediate the difference of cortical synchronization between Parkinson’s disease patients and normal controls. Finally, we found decreases in synchronization of each cortical networks is correlated to impairment in its structural connectivity to thalamus and caudate. Together, these results highlight diminished dopaminergic function and the pathological changes in thalamus related structures responsible for decreased cortical synchronization and metastability, further affect cognitive function in Parkinson’s disease.

Acknowledgements

We thank all patients with Parkinson’s disease patients and healthy controls who participated in this study.

References

Aarsland, D., Creese, B., Politis, M., Chaudhuri, K. R., Ffytche, D. H., Weintraub, D., & Ballard, C. (2017). Cognitive decline in Parkinson disease. Nat Rev Neurol, 13(4), 217-231. doi:10.1038/nrneurol.2017.27

Alderson, T. H., Bokde, A. L. W., Kelso, J. A. S., Maguire, L., & Coyle, D. (2018). Metastable neural dynamics in Alzheimer's disease are disrupted by lesions to the structural connectome. NeuroImage, 183, 438-455. doi:10.1016/j.neuroimage.2018.08.033

Oh, S. W., Harris, J. A., Ng, L., Winslow, B., Cain, N., Mihalas, S., . . . Zeng, H. (2014). A mesoscale connectome of the mouse brain. Nature, 508(7495), 207-214. doi:10.1038/nature13186

Shine, J. M., Bell, P. T., Matar, E., Poldrack, R. A., Lewis, S. J. G., Halliday, G. M., & O'Callaghan, C. (2019). Dopamine depletion alters macroscopic network dynamics in Parkinson's disease. Brain, 142(4), 1024-1034. doi:10.1093/brain/awz034

Figures

Procedure Flowchart illustrating the different steps of analysis with the fMRI data and its results. (A) An overview of the adapted analysis paradigm in this study. (B) Cortical synchronization and metastability in normal controls (NC) and Parkinson’s disease patients (PD). (C) Cortical synchronization and metastability in Parkinson’s disease in both the OFF and ON states.

Relationship between cortical synchronization and metastability and MoCA score. (A) Relationship between cortical synchronization of fMRI BOLD signal and MMSE score. (B) Relationship between cortical metastability of fMRI BOLD signal and MoCA score. Mediation model using group label as the predictor, cortical synchronization (C) and metastability (D) as the mediators, and MoCA score as the dependent variable. Group labels are categorical label of normal controls (NC) and PD, where NC were set as 0, PD were set as 1. ** P < 0.05, ** P <.01, *** P < 0.001.

Relationship between cortical synchronization/metastability with thalamus grey matter volume and thalamocortical connectivity. (A, B) Relationship between cortical synchronization/metastability and thalamus volume/thalamocortical connectivity. (C, D) Mediation model using group label as the predictor, thalamus volume and thalamocortical connectivity PC1 as the mediator, and cortical synchronization as the dependent variable. Group labels are categorical label of NC and PD, where NC were set as 0, PD were set as 1. ** P < 0.05, ** P <0.01, *** P < 0.001.

Relationships between synchronization of networks and subcortical-cortical structural connectivity disruption. (A) Synchronization analyses within and between the seven networks delineated by Yeo et al. (B) Metastability analyses within and between the seven networks. (C) Thalamocortical connectivity in PD vs NC in the seven brain networks. Correlation between decreases in synchronization (C) and metastability (D) (average t-values, PD–NC) of each brain networks and the degree of reduction connectivity between thalamus and each network (average t-values, PD–NC).

Relationship between cortical synchronization and metastability and MMSE score. (A) Relationship between cortical synchronization of fMRI BOLD signal and MMSE score. (B) Relationship between cortical metastability of fMRI BOLD signal and MMSE score. Mediation model using group label as the predictor, cortical synchronization (C) and metastability (D) as the mediators, and MMSE score as the dependent variable. Group labels are categorical label of normal controls (NC) and PD, where NC were set as 0, PD were set as 1. ** P < 0.05, ** P <.01, *** P < 0.001.

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)

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