Abnormal Phase Coupling in Parkinson's Disease and Normalization Effects of Subthreshold Vestibular Stimulation

The human brain is a highly dynamic structure requiring dynamic coordination between different neural systems to perform numerous cognitive and behavioral tasks. Emerging perspectives on basal ganglia (BG) and thalamic functions have highlighted their role in facilitating and mediating information transmission among cortical regions. Thus, changes in BG and thalamic structures can induce aberrant modulation of cortico-cortical interactions. Recent work in deep brain stimulation (DBS) has demonstrated that externally applied electrical current to BG structures can have multiple downstream effects in large-scale brain networks. In this work, we identified EEG-based altered resting-state cortical functional connectivity in Parkinson's disease (PD) and examined effects of dopaminergic medication and electrical vestibular stimulation (EVS), a non-invasive brain stimulation (NIBS) technique capable of stimulating the BG and thalamus through vestibular pathways. Resting EEG was collected from 16 PD subjects and 18 age-matched, healthy controls (HC) in four conditions: sham (no stimulation), EVS1 (4-8 Hz multisine), EVS2 (50-100 Hz multisine) and EVS3 (100-150 Hz multisine). The mean, variability, and entropy were extracted from time-varying phase locking value (PLV), a non-linear measure of pairwise functional connectivity, to probe abnormal cortical couplings in the PD subjects. We found the mean PLV of Cz and C3 electrodes were important for discrimination between PD and HC subjects. In addition, the PD subjects exhibited lower variability and entropy of PLV (mostly in theta and alpha bands) compared to the controls, which were correlated with their clinical characteristics. While levodopa medication was effective in normalizing the mean PLV only, all EVS stimuli normalized the mean, variability and entropy of PLV in the PD subject, with the exact extent and duration of improvement a function of stimulus type. These findings provide evidence demonstrating both low- and high-frequency EVS exert widespread influences on cortico-cortical connectivity, likely via subcortical activation. The improvement observed in PD in a stimulus-dependent manner suggests that EVS with optimized parameters may provide a new non-invasive means for neuromodulation of functional brain networks.