Large-scale network dysfunction in α-Synucleinopathy: A meta-analysis of resting-state functional connectivity

BACKGROUND: Although dysfunction of large-scale brain networks has been frequently demonstrated in patients with α-Synucleinopathy (α-Syn, i.e., Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy), a consistent pattern of dysfunction remains unclear. We aim to investigate network dysfunction in patients with α-Syn through a meta-analysis. METHODS: Whole-brain seed-based resting-state functional connectivity studies (published before September 1st, 2020 in English) comparing α-Syn patients with healthy controls (HC) were retrieved from electronic databases (PubMed, Web of Science, and EMBASE). Seeds from each study were categorized into networks by their location within a priori functional networks. Seed-based effect size mapping with Permutation of Subject Images analysis of between-group effects identified the network systems in which α-Syn was associated with hyperconnectivity (increased connectivity in α-Syn vs. HC) or hypoconnectivity (decreased connectivity in α-Syn vs. HC) within and between each seed-network. This study was registered on PROSPERO (CRD42020210133). FINDINGS: In total, 136 seed-based voxel-wise resting-state functional connectivity datasets from 72 publications (3093 α-Syn patients and 3331 HC) were included in the meta-analysis. We found that α-Syn patients demonstrated imbalanced connectivity among subcortical network, cerebellum, and frontal parietal networks that involved in motor functioning and executive control. The patient group was associated with hypoconnectivity in default mode network and ventral attention network that involved in cognition and attention. Additionally, the patient group exhibited hyperconnectivity between neural systems involved in top-down emotion regulation and hypoconnectivity between networks involved in bottom-up emotion processing. INTERPRETATION: These findings supported neurocognitive models in which network dysfunction is tightly linked to motor, cognitive and psychiatric symptoms observed in α-Syn patients.