Abstract
Parkinson's disease (PD) is primarily characterized by the loss of dopaminergic cells and atrophy in subcortical regions. However, the impact of these pathological changes on large‐scale dynamic integration and segregation of the cortex are not well understood. In this study, we investigated the effect of subcortical dysfunction on cortical dynamics and cognition in PD. Spatiotemporal dynamics of the phase interactions of resting‐state blood‐oxygen‐level‐dependent signals in 159 PD patients and 152 normal control (NC) individuals were estimated. The relationships between subcortical atrophy, subcortical–cortical fiber connectivity impairment, cortical synchronization/metastability, and cognitive performance were then assessed. We found that cortical synchronization and metastability in PD patients were significantly decreased. To examine whether this is an effect of dopamine depletion, we investigated 45 PD patients both ON and OFF dopamine replacement therapy, and found that cortical synchronization and metastability are significantly increased in the ON state. The extent of cortical synchronization and metastability in the OFF state reflected cognitive performance and mediates the difference in cognitive performance between the PD and NC groups. Furthermore, both the thalamic volume and thalamocortical fiber connectivity had positive relationships with cortical synchronization and metastability in the dopaminergic OFF state, and mediate the difference in cortical synchronization between the PD and NC groups. In addition, thalamic volume also reflected cognitive performance, and cortical synchronization/metastability mediated the relationship between thalamic volume and cognitive performance in PD patients. Together, these results highlight that subcortical dysfunction and reduced dopamine levels are responsible for decreased cortical synchronization and metastability, further affecting cognitive performance in PD. This might lead to biomarkers being identified that can predict if a patient is at risk of developing dementia.
Highlights
Parkinson's disease (PD) is characterized by aggregation of degenerated α-synuclein in the substantia nigra pars compacta and striatal dopaminergic deficiency, resulting in the cardinal motor symptoms associated with PD (Aarsland et al, 2017)
To examine the causal role of dopamine depletion in cortical synchronization and metastability, we evaluated whether levodopa could modulate cortical synchronization and metastability in PD patients
To test whether cortical synchronization and metastability are associated with cognitive performance, we tested for a correlation of cortical synchronization and metastability with Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores. We found both cortical synchronization and metastability positively correlated with MMSE (Figure 2a,b) and MoCA (Figure S4a,b) scores in the OFF state of PD patients (p < .05, FDR corrected), suggesting that lower cortical synchronization and metastability was associated with poorer cognitive performance
Summary
Parkinson's disease (PD) is characterized by aggregation of degenerated α-synuclein in the substantia nigra pars compacta and striatal dopaminergic deficiency, resulting in the cardinal motor symptoms associated with PD (Aarsland et al, 2017). Cognitive impairment in PD does not merely involve neurotransmitter deficits, which is characterized by altered networks of brain structures as aggregation of degenerated α-synuclein spreads from subcortical to cortical regions (Pandya et al, 2019; Yau, Zeighami, Baker, Larcher, & Vainik, 2018). A dynamic balance between functional integration and segregation of large-scale brain networks is essential for a range of cognitive processes (Alderson, Bokde, Kelso, Maguire, & Coyle, 2020; Bell & Shine, 2016; Deco & Kringelbach, 2016). Dysfunction of subcortical regions in PD patients might contribute to abnormal functional integration and segregation of cortical networks.
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