Delta-Beta and Beta-Gamma Coupling as Biomarkers of Medication Efficacy in Parkinson's Disease

Parkinson’s disease (PD) is marked by neural synchronization, with cross-frequency interactions such as phase-amplitude coupling (PAC) believed to underpin its motor and non-motor symptoms. While invasive studies implicate beta-gamma PAC in PD pathophysiology, the feasibility of detecting and characterizing these dynamics non-invasively and their modulation by therapy remains underexplored. This pilot study investigates nested PAC across delta, beta, and gamma bands in PD using scalp EEG, aiming to identify PD-specific coupling patterns and evaluate their responsiveness to dopaminergic medication. EEG data from PD patients and healthy controls were analyzed using PAC metrics. We examined interactions between delta (0.5–4 Hz), beta (13–30 Hz), and gamma (30–110 Hz) bands pre- and post-medication, with rigorous artifact rejection to confirm coupling specificity. Unmedicated PD patients exhibited delta-beta and beta-gamma PAC which were attenuated following dopaminergic therapy. Notably, delta-beta coupling persisted in the majority of patients, suggesting that delta oscillations may play an underrecognized role in sustaining pathological interactions. These findings reveal a sequential hierarchy in which delta-phase organizes beta activity, which subsequently modulates gamma amplitude, a cascading mechanism disrupted by medication. This work provides preliminary evidence that non-invasive EEG can capture PD-specific PAC dynamics, linking delta-band activity to motor dysfunction. The suppression of pathological couplings post-therapy highlights delta-beta PAC’s potential as a biomarker for treatment efficacy. While further validation is required, these results advocate for expanded investigations into nested cross-frequency interactions, paving the way for neuromodulatory strategies that target oscillatory network dysfunction in PD.