Brain Plasticity induced by Vagal Nerve Stimulation in Patients affected by Drug-resistant Epilepsy: effects on Brain Network and Neurotrophins

Chronic Vagal Nerve Stimulation (VNS) is an approved neuromodulation therapy that is effective in the treatment of drug-resistant epilepsy (DRE). Despite the high number of devices implanted and subjects treated (over 100,000), the exact mechanism of action is still debated in the literature: widespread effects on neurotransmitter expression, blood flow, brain network and EEG, neuroinflammation, and neurotrophins (e.g. BDNF and NGF) have been proposed as key to understanding the efficacy of VNS on seizure frequency, psychiatric symptoms, memory, and quality of life of DRE subjects. Neuroplasticity is the ability of the human brain to reorganize its functions in response to any experience. Several pathways are activated to lead to short- and long-term changes and a central role is played by neurotrophins, including BDNF. The action of the latter is negatively affected by the presence of the Val66Met polymorphism. The analysis of the human brain according to a network perspective allows studying its functional connections and their modifications, for example by the use of EEG. The study of EEG aperiodic components allows to analyze the basic brain activity, specific to the individual. The mechanisms of brain plasticity represent the neurophysiological substrate that leads to modifications in the brain network. Based on these premises, this study aims to analyze the effects of VNS on brain plasticity of DRE subjects, through the study of high-density EEG brain network and the BDNF expression. Furthermore, it aims to infer how the clinical outcome of VNS therapy is affected by the presence of the Val66Met polymorphism. In order to do so, we investigated (1) the change in functional connectivity and aperiodic EEG components after one year of VNS chronic therapy, and its correlation with clinical response, (2) the clinical response to VNS in subjects with and without BDNF Val66Met polymorphism, and (3) the expression of serum BDNF during VNS titration and its correlation with the presence of the polymorphism. The results showed that: (1) VNS therapy modifies the brain network differently in responder and non-responder subjects, and changes in aperiodic components correlate with the clinical response; (2) clinical response to VNS is worse in subjects carrying the Val66Met polymorphism; and (3) serum BDNF expression is variable across subjects during VNS titration. Thus, this study paves the way to the analysis of the effect of VNS on the brain background rhythm through aperiodic components and to the identification of a predictive factor of clinical response in the BDNF Val66Met polymorphism. Future directions will be aimed to the sample size enlargement and to the analysis of clinical outcomes more suitable to evaluate all the beneficial effects of VNS, to understand even better the mechanism of action of this neuromodulation technique.