Vagal Nerve Stimulation: The Effect on the Brain Oscillatory Field Potential.

More than thirty years of medical treatment with the use of vagal nerve stimulation (VNS) has shown that this therapeutic procedure works in a number of homeostatic disturbances. Although the clinical usage of VNS has a long history, our knowledge about the central mechanisms underlying this treatment is still limited. In the present paper we review the effects of VNS on brain oscillations as a possible electrophysiological bio-marker of VNS efficacy. The review was prepared mainly on the basis of data delivered from clinical observations and the outcomes of electrophysiological experiments conducted on laboratory animals that are available in PubMed. We consciously did not focus on epileptiform activity understood as a pathologic oscillatory activity, which was widely discussed in the numerous previously published reviews. The main conclusion of the present paper is that further, well-designed experiments on laboratory animals are absolutely necessary to address the electrophysiological issues. These will fill a number of gaps in our present knowledge of the central mechanisms underlying VNS therapy.

Hippocampal theta rhythm induced by vagal nerve stimulation: The effect of modulation of electrical coupling.

Previously we have demonstrated that vagal nerve stimulation (VNS) is capable of inducing hippocampal formation (HPC) theta rhythm (Broncel et al., 2017). The neuronal substrate underlying this novel phenomenon is poorly known, though the cholinergic and GABAergic profile of VNS-induced theta rhythm in anesthetized rats has just recently been addressed (Broncel et al., 2018a, 2019). In this study we extended our earlier observation concerning the pharmacological profile of VNS-induced theta oscillations. Specifically, the purpose of the present study was to test the hypothesis that VNS-induced hippocampal theta rhythm could be modulated by local HPC gap junctions (GJs) transmission. Two GJs agents were used: carbenoxolone, nonspecific GJs blocker and trimethylamine, a nonspecific opener of GJs. Two basic parameters of theta rhythm were evaluated: frequency and power. It was demonstrated that carbenoxolone inhibits VNS-induced theta while trimethylamine facilities it. These observations indicate that HPC electrical coupling mediates the theta rhythm induced by vagal nerve stimulation.

GABAergic mediation of hippocampal theta rhythm induced by stimulation of the vagal nerve.

The key question to be answered in the present study was whether the medial septal GABAergic receptors are engaged in the pharmacological profile of the hippocampal formation (HPC) theta rhythm induced by vagal nerve stimulation (VNS). It was demonstrated that the medial septal microinfusion of GABAA and GABAB agonists (muscimol and baclofen) resulted in a progressive reduction of the power of VNS-induced theta. The medial septal microinfusion of GABAA and GABAB antagonists (bicuculline and 2-OH saclofen) resulted in the generation of VNS-induced theta with increased power. The effect of the combined medial septal microinfusion of GABAA agonist and antagonist and GABAB agonist and antagonist on VNS-induced theta rhythm was also evaluated: in the presence of GABAA,B antagonists the effect of agonists predominated. In separate experiments, GABAA and GABAB antagonists were administrated in anesthetized rats pretreated with i.v. administration of atropine sulfate. Atropine was found to abolish spontaneous theta and VNS-induced theta examined in the presence of bicuculline or 2-OH saclofen. The present data provide evidence that the medial septal GABAA and GABAB receptors are involved in the central mechanisms responsible for modulation of VNS-induced HPC theta oscillations. Furthermore, the results of the present study also demonstrate that, in fact, both GABAergic and cholinergic involvement is necessary for the appearance of VNS-induced theta.

Medial septal cholinergic mediation of hippocampal theta rhythm induced by vagal nerve stimulation.

BACKGROUND: Electrical vagal nerve stimulation (VNS) has been used for years to treat patients with drug-resistant epilepsy. This technique also remains under investigation as a specific treatment of patients with Alzheimer's disease. Recently we discovered that VNS induced hippocampal formation (HPC) type II theta rhythm, which is involved in memory consolidation. In the present study, we have extended our previous observation and addressed the neuronal substrate and pharmacological profile of HPC type II theta rhythm induced by VNS in anesthetized rats. METHODS: Male Wistar rats were implanted with a VNS cuff electrode around the left vagus nerve, a tungsten microelectrode for recording the HPC field activity, and a medial septal (MS) cannula for the injection of a local anesthetic, procaine, and muscarinic agents. A direct, brief effect of VNS on the HPC field potential was evaluated before and after medial-septal drug injection. RESULTS: Medial septal injection of local anesthetic, procaine, reversibly abolished VNS-induced HPC theta rhythm. With the use of cholinergic muscarinic agonist and antagonists, we demonstrated that medial septal M1 receptors are involved in the mediation of the VNS effect on HPC theta field potential. CONCLUSION: The MS cholinergic M1 receptor mechanism integrates not only central inputs from the brainstem synchronizing pathway, which underlies the production of HPC type II theta rhythm, but also the input from the vagal afferents in the brain stem.

Some technical issues of vagal nerve stimulation. An approach using a hippocampal formation theta rhythm.

Previously, we have demonstrated that hippocampal (HPC) theta rhythm can be produced, depending on current intensity, directly during vagal nerve stimulation (VNS) or with a time delay following stimulation. This suggests that theta EEG pattern can also be used as a bio-indicator of the efficiency of VNS. In the present study, we focused on three specific, technical issues related to the stimulation procedure of the vagal nerve: i/does the type of the electrode used for VNS and the technique of its implantation affect the parameters of the HPC theta rhythm? ii/does the type of electrode used determine the current intensity threshold of VNS-induced HPC theta? iii/is the repeatability of the VNS effect determined by the type of electrode used? We demonstrated that a platinum-iridium cuff electrode offers some important advantages over a tungsten electrode. Firstly, despite some possible mechanical and compression nerve damage related to permanent contact with the vagal nerve, it offers a lower current intensity threshold for inducing theta oscillations. Secondly, and most importantly, the cuff electrode offers repeatability of the VNS effect on the HPC theta rhythm. However, one disadvantage of using this type of an electrode is that the permanent pressure on the vagal nerve by the cuff itself may decrease the amplitude of the investigated field potential.

Vagus nerve stimulation produces a hippocampal formation theta rhythm in anesthetized rats.

Vagus nerve stimulation (VNS) has been used for years to treat patients with drug-resistant epilepsy. In the present study, the effect of different stimulation protocols of VNS on the hippocampal formation (HPC) type II theta field potentials were evaluated in anesthetized rats. The following theta parameters were analysed: power, frequency and duration of theta epochs. We documented for the first time the presence of HPC type II theta in response to the application of VNS. A VNS-induced theta rhythm appeared in different experimental protocols and, depending on the current intensity, could occur directly during VNS (brief effect) or after vagal stimulation (delayed effect), using lower intensity stimuli.