Transcutaneous Vagal Nerve Stimulation (tVNS): a new neuromodulation tool in healthy humans?

The idea that we can influence neurons with electricity is not new. Earlier this century patients were treated, and still are, with electro convulsive therapy as a treatment for severe depression (Fink, 1984). Fortunately, new devices were invented that use electricity to influence neuronal activity in a less invasive way: transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and vagus nerve stimulation (VNS). In contrast to imaging techniques, which are only correlational, by means of these techniques it is possible to infer a causal relation between the stimulated neurotransmitter/brain area and a related cognitive function. Recently, Cerbomed (Erlangen, Germany) engineered a noninvasive, transcutaneous (through the skin) VNS device (tVNS) that stimulates the afferent auricular branch of the vagus nerve located medial of the tragus at the entry of the acoustic meatus (Kreuzer et al., 2012). This device has received CE approval as indication that it complies with essential health and safety requirements. Thus, tVNS is safe and accompanied only by minor side effects such as slight pain, burning, tingling, or itching sensation under the electrodes. Nevertheless, as specified in the instructions manual, the use of the device is contraindicated in the case of pregnancy, cardiac diseases, head trauma, alcoholism, migraine, medication or drug use, neurological or psychiatric disorders, metal pieces in the body (pacemaker), active implants such as a cochlear implant, wounds and diseased skin. A number of studies using high intensity tVNS have not found any major side-effects (Kraus et al., 2007; Dietrich et al., 2008). Given that the right vagal nerve has efferent fibers to the heart, tVNS is safe to be performed only in the left ear (Sperling et al., 2010; Kreuzer et al., 2012). Following Kraus et al. (2007), a clever way to create a sham condition using tVNS is by attaching the stimulation electrodes to the center of the left ear lobe, which is known to be free of cutaneous vagal innervation (Peuker and Filler, 2002), see Figure ​Figure1.1. Indeed, a recent functional magnetic resonance imaging (fMRI) study showed that this sham condition produced no activation in the cortex and brain stem (Kraus et al., 2013). Figure 1 Positioning of the stimulation electrodes in the active (left) and in the sham (right) condition. So far, VNS has been used to study cognitive functioning only in patients with epilepsy and major depression (Vonck et al., 2014). However, the focus of the present opinion article is not on clinical populations but on healthy humans and how tVNS may be a useful tool to further investigate the neuromodulation of cognitive processes related to norepinephrine (NE), gamma-aminobutyric acid (GABA) and Acetylcholine (ACh), the three main neurotransmitters targeted by VNS. To this end we discuss a number of NE, GABA, and ACh-related cognitive functions that could be modulated by tVNS. This is by no means an exhaustive list; the aim of this opinion article is rather to point out and highlight some theoretically driven links that may help to improve designing future tVNS studies. So far, the studies discussed below have not yet been investigated in combination with tVNS in healthy humans. However, based on literature that details their relation to NE and GABA functions we argue that these studies will prove fertile for future research.