EEG functional connectivity is modulated by vagus nerve stimulation in drug-resistant epilepsy

Introduction Drug-resistant epilepsy is characterized by the failure to achieve sustained seizure freedom despite adequate trials of at least two well-tolerated, appropriately chosen, and properly administered antiseizure medications. Approximately 30% of people with epilepsy (PwE) develop this condition, which is associated with substantial clinical burden, including cognitive impairment, psychiatric comorbidities, increased mortality risk, and significant social consequences. For patients who are not candidates for epilepsy surgery, neuromodulation represents a potential therapeutic alternative for managing drug resistance. Among available neuromodulation strategies, invasive vagus nerve stimulation (VNS) has been shown to be both effective and safe; however, its precise mechanisms of action remain incompletely understood. Objectives and Methods We performed a longitudinal study to investigate the neuromodulatory effects of VNS on large-scale brain network organization in PwE by using quantitative electroencephalography (qEEG). Ten adult patients underwent high-density EEG recordings before VNS implantation (T0) and after 12 months of therapy (T1). Functional connectivity and spectral properties were analyzed across different conditions, including resting-state activity without epileptiform discharges (BG_OFF), active stimulation periods (BG_ON), and interictal epileptiform events (Spikes_OFF and Spikes_ON). Clinical outcomes were assessed throughout seizure frequency reduction and global measures of improvement. Results Results demonstrated a significant reduction in global functional connectivity over time during resting-state (BG_OFF) conditions (p<0.001), suggesting a modulation of baseline network activity. Additionally, interictal spike-related connectivity significantly decreased in both OFF and ON conditions (p<0.001 for both conditions), indicating a reduced propensity for epileptiform activity propagation. No significant connectivity changes were observed during active stimulation alone, and spectral power analysis did not reveal statistically significant differences across frequency bands, although a non-significant trend toward increased theta activity was noted. Clinically, none of the patients achieved seizure freedom, while 30% met criteria for seizure responsiveness (≥50% reduction). However, when broader outcome measures were considered, 70% of patients were classified as having a favorable outcome, including improvements in seizure severity and quality of life. No significant association was found between electrophysiological changes and clinical outcome groups. Conclusions These findings support the conceptualization of epilepsy as a network disorder and suggest that VNS exerts its therapeutic effects by progressively modulating dysfunctional brain connectivity, both during and beyond active stimulation periods. The observed reduction in global and interictal connectivity may reflect decreased synchronization within epileptogenic networks, potentially limiting seizure generation and spread. Despite limitations including small sample size and modest responder rate, this study highlights the potential of qEEG-derived functional connectivity as a biomarker for VNS response. Further large-scale studies with extended follow-up are needed to validate these findings and clarify the relationship between neurophysiological changes and clinical outcomes.