Maccabeo, Alessandra MD; Salustro, Emanuela MD; Sanna, Mauro MD; Garau, Pietro MD; Maioli, Maria Antonietta MD, PhD; Coa, Roberta MD, PhD; Puligheddu, Monica MD, PhD; Borghero, Giuseppe MD Author Information

Neuromodulation by means of vagus nerve stimulation (VNS) therapy, reduces seizure frequency and improves quality of life in subjects with drug-resistant epilepsy (DRE), yet its molecular mechanism remains unclear. This study investigates the impact of chronic VNS on lipid bioactive metabolites and fatty acids (FA) in the plasma and red blood cells of seven subjects with DRE. By measuring expression levels of peroxisome proliferator-activated receptor α (PPARα) and sirtuin1 (SIRT1) genes-key regulators in energy and lipid metabolism-and lipid profiles before and after various stages of VNS, this study identifies potential mechanisms by which VNS may reduce seizure frequency. Blood samples collected before VNS device implantation, after acute VNS stimulus, and following gradual intensity increments up to therapeutic levels revealed that VNS increases SIRT1 and PPARα expression and erythrocyte concentrations of PPARα ligands. Additionally, we observe reduced de novo lipogenesis biomarkers in erythrocytes, indicating that VNS may influence systemic lipid and energy metabolism. Our findings suggest that VNS could enhance neuronal function by modulating energy metabolism, thus potentially reducing seizure frequency in subjects with DRE. Future research targeting SIRT1 and PPARα may provide innovative therapeutic strategies for managing DRE. Plain Language Summary: The exact mechanism of VNS is still unknown. This study investigated the effects of VNS Therapy on energetic metabolism, suggesting possible novel biomarkers for DRE subjects and neuromodulation therapies.

Vagal nerve stimulation (VNS) is safe and effective in adults and children with epilepsy according to FDA. Brain-derived Neurotrophic Factor (BDNF) is implicated in many neurophysiological processes and exerts effects on hippocampal serotonergic pathways during both acute and chronic VNS stimulation.1 BDNF gene encodes a precursor peptide (proBDNF) and non-conservative single nucleotide polymorphism (SNP) has been identified in humans producing an amino acid substitution (Val66Met). This SNP affects intracellular processing and secretion of BDNF, leading to impaired hippocampal function in humans.

BackgroundVagal nerve stimulation (VNS) improves seizure frequency and quality of life in patients with drug-resistant epilepsy (DRE), although the exact mechanism is not fully understood. Previous studies have evaluated the effect of VNS on functional connectivity using the phase lag index (PLI), but none has analyzed its effect on EEG aperiodic parameters (offset and exponent), which are highly conserved and related to physiological functions.ObjectiveThis study aimed to evaluate the effect of VNS on PLI and aperiodic parameters and infer whether these changes correlate with clinical responses in subjects with DRE.Materials and methodsPLI, exponent, and offset were derived for each epoch (and each frequency band for PLI), on scalp-derived 64-channel EEG traces of 10 subjects with DRE, recorded before and 1 year after VNS. PLI, exponent, and offset were compared before and after VNS for each patient on a global basis, individual scalp regions, and channels and separately in responders and non-responders. A correlation analysis was performed between global changes in PLI and aperiodic parameters and clinical response.ResultsPLI (global and regional) decreased after VNS for gamma and delta bands and increased for an alpha band in responders, but it was not modified in non-responders. Aperiodic parameters after VNS showed an opposite trend in responders vs. non-responders: both were reduced in responders after VNS, but they were increased in non-responders. Changes in aperiodic parameters correlated with the clinical response.ConclusionThis study explored the action of VNS therapy from a new perspective and identified EEG aperiodic parameters as a new and promising method to analyze the efficacy of neuromodulation.

An association between the induction of neuronal plasticity and effects of Vagal Nerve Stimulation (VNS) on Drug-Resistant Epilepsy (DRE) has been hypothesized but not fully demonstrated in humans.1 Long-term plasticity is the neurophysiological correlate of changes in the brain network.2 Functional connectivity (Fc) describes statistical dependency patterns of different electrodes in selected time series through different metrics:3 among them, Phase Lag Index (PLI) quantifies the asymmetry of distribution of phase differences between two signals, represents the synchronization of the EEG signal4 and is poorly affected by interference from the use of a scalp signal.

Increased sleep instability and reduced sleep quality are both features and promoting factors for sleep-related hypermotor epilepsy (SHE) and disorders of arousal (DOA). We aimed to compare subjective sleep quality, objective sleep features and cognitive-behavioral profile in patients with SHE and DOA.