Loehrer, P. A.; Yassine, S.; Weber, I.; Sanner, V.; He, S. A.; Pogosyan, A.; Chen, L.; Witt, L.; Fink, G. R.; Pedrosa, D. J.; Timmermann, L.; Tan, H.

Cross-frequency coupling (CFC) has been proposed to facilitate neural information transfer across spatial and temporal scales. Phase-amplitude coupling (PAC), a type of CFC in which the amplitude of a faster brain oscillation is coupled to the phase of a slower brain oscillation, is implicated in various higher-order cognitive functions and was shown to be pathologically altered in neurological and psychiatric disease. In Parkinson\'s disease (PD), the coupling between gamma amplitude (50-150 Hz) to beta phase (13-35 Hz) is exaggerated. Enhanced {beta}-{gamma} PAC was found in the subthalamic nucleus and various cortical sources and shown to be responsive to dopaminergic therapy and deep brain stimulation (DBS). Therefore, exaggerated {beta}-{gamma} PAC has been proposed to be a disease marker and a potential target for brain circuit interventions. Despite these promising findings, a significant knowledge gap remains, as the spatial and frequency-specific dynamics of {beta}-{gamma} PAC and its association with motor symptoms and therapy remain elusive. To address this knowledge gap, we employed high-density electroencephalography (EEG) with advanced source localisation techniques for PD patients at rest. We highlight three key findings: (1) a frequency-specific increase in high {beta} (23-35 Hz)-{gamma} PAC within and between sources of the cortical motor network, (2) a link between elevated high {beta}-{gamma} PAC and bradykinesia and rigidity when OFF medication, but not tremor, and (3) a medication-induced reduction in high {beta}-{gamma} PAC in the supplementary motor area correlating with clinical improvement. Altogether, this study provides novel insights into the pathophysiology of PD as an oscillopathy and identifies high {beta}-{gamma} PAC as a potential marker of Parkinsonian symptoms and treatment effects. This has important implications for invasive as well as non-invasive therapeutic strategies as high {beta}-{gamma} PAC targeting might hold greater promise than targeting {beta}-{gamma} PAC per se.