The Effectiveness of Vagus Nerve Stimulation in Drug-Resistant Epilepsy Correlates with Vagus Nerve Stimulation-Induced Electroencephalography Desynchronization

Abstract

Aim: To investigate electroencephalographic (EEG) metrics of functional connectivity in patients with drugrefractory epilepsy treated by vagus nerve stimulation (VNS), between VNS-stimulated ''ON'' and nonstimulated ''OFF'' periods and between responder (R) and nonresponder (NR) patients. Introduction: VNS is an adjunctive neuromodulation therapy for patients with drug-refractory epilepsy. The antiseizure effect of VNS is thought to be related to a diffuse modulation of functional connectivity but remains to be confirmed. Methods: Scalp-EEG was performed for 35 patients treated by VNS, using 21 channels and 2 additional electrodes on the neck to detect the VNS stimulation. Patients were defined as VNS responders if a reduction of seizure frequency of *50% was documented. We analyzed the synchronization in EEG time series during ''ON'' and ''OFF'' periods of stimulation, using average phase lag index (PLI) in signal space and phase-locking value (PLV) between 10 sources. Based on graph theory, we computed brain network models and analyzed minimum spanning tree (MST) for responder and nonresponder patients. Results: Among 35 patients treated by VNS for a median time of 7 years (range 4 months to 22 years), 20 were R and 15 were NR. For responder patients, PLI during ON periods was significantly lower than that during OFF periods in delta (p = 0.009), theta (p = 0.02), and beta (p = 0.04) frequency bands. For nonresponder patients, there were no significant differences between ON and OFF periods. Moreover, variations of seizure frequency with VNS correlated with the PLI OFF/ON ratio in delta (p = 0.02), theta (p = 0.04), and beta (p = 0.03) frequency bands. Our results were confirmed using PLV in theta band (p < 0.05). No significant differences in MST were observed between R and NR patients. Conclusion: The correlation between VNS-induced interictal EEG time-series desynchronization and decrease in seizure frequency suggested that VNS therapeutic impact might be related to changes in interictal functional connectivity.

Prediction of the Responsiveness to Vagus-Nerve Stimulation in Patients with Drug-Resistant Epilepsy via Directed-Transfer-Function Analysis of Their Perioperative Scalp EEGs

“…However, no consistent changes in connectivity were detected in the stimulation-on state vs. the stimulation-off state. This result differed from that of the previous literature, which reported global desynchronization with PLI values when the stimulation was on in the responder group compared with those when the stimulation was off [16,23,24]. This finding may be attributed to a different time interval between surgery and the EEG study, or a different methodology of EEG analysis employed in the previous studies compared with ours.…”

“…For the prediction of responsiveness to VNS, it is essential to identify an appropriate prognostic metric that can be recorded preoperatively. Although Fraschini et al reported a lack of differences in the phase lag index (PLI) between the responder and nonresponder groups before VNS [21], other studies did not report the presurgical PLI values [23,24]. Babajani-Feremi et al first investigated the prediction of VNS outcome based on MEG data acquired before the implantation of VNS, and revealed that the nonresponders exhibited a higher transitivity and lower modularity derived from graph measures than the responders [25].…”

Latest Views on the Mechanisms of Action of Surgically Implanted Cervical Vagal Nerve Stimulation in Epilepsy

“…There also is some evidence showing that chronic VNS influences network measures. Fraschini et al 82 reported significant effects of long-term VNS on Minimum Spanning Tree in responders with a more integrated/efficient global network, results that were, however, not replicated by Sangare et al, 86 and Vespa et al 87 showed a stronger decrease of global efficiency during sleep in responders than in nonresponders.…”

Transcranial current stimulation in epilepsy: A systematic review of the fundamental and clinical aspects

“…Recent studies indeed demonstrated that global brain network dynamics are linked to clinical outcome of pharmacological antiepileptic treatments and that such epilepsy-related FC changes are reversible and can be controlled by AEDs (Clemens et al, 2014 ; Anderson et al, 2020 ). As far as neurostimulation is concerned, clinical studies using invasive neuromodulatory devices, such as vagus nerve stimulation (VNS) have shown a decreased synchrony induced by VNS as anti-epileptic mechanism in patients with good response (Fraschini et al, 2013 ; Bodin et al, 2015 ; Sangare et al, 2020 ).…”