Vagus nerve stimulation (VNS) is a neurostimulation method that consists of stimulating the vagus nerve with regular, mild pulses of electrical energy. VNS was first applied to humans in clinal trials in the 1990s, showing potential for the treatment of epilepsy (Penry & Dean, 1990). The technique has since been tested for the treatment of several diseases, and nowadays its use is widespread, with more than 70,000 patients being treated with VNS by 2013 (Labiner & Ahern, 2007). VNS is approved by the US Food and Drug Administration (FDA) for the treatment of treatment-resistant epilepsy and depression.
Traditionally, VNS was performed by a device implanted around the chest and neck that wrapped a stimulating electrode around the cervical vagus nerve (Johnson & Wilson, 2018). This required anesthesia and surgery, with its associated risk and high cost. In recent years, transcutaneous (i.e. through the skin) vagus nerve stimulation (tVNS) has been developed, an alternative non-invasive method. Instead of targeting the cervical vagus nerve, tVNS applies electrical impulses directly to the outer ear, where the cutaneous fibers of the vagus nerve are located (Butt et al., 2020; Yakunina et al., 2017). The mechanism of action and effects of tVNS are the same as traditional invasive VNS, and it has been shown to achieve similar brain activation patterns (Ellrich, 2019). A big advantage of tVNS is its simplicity, and nowadays several tVNS devices are commercially available (https://vagus.net).
In the last decade, several scientific studies have shown the potential of tVNS for the treatment of several diseases, including epilepsy, depression, obesity, dementia, chronic pain, tinnitus, and heart failure. In addition, tVNS has been shown to improve cognition and provide physical benefits to healthy individuals, for instance, improved cognitive control, emotion recognition and regulation, language learning, and associative memory.
The vagus nerve (10th cranial nerve) is the longest autonomic nerve in the human body and innervates several major organs, including heart, lungs, liver, and intestines (Berthoud & Neuhuber, 2000). Its main functions are the parasympathetic control over the heart and lungs, and controlling inflammatory processes through the cholinergic pathway. 80% of vagus nerve fibers transfer information from organs to the brain (afferent fibers), and 20% send signals from the brain to the body (efferent fibers).
Figrure 1. Anatomy of the Vagus nerve
The anatomy of the vagus nerve and the organs and tissues it innervates can be seen in Figure 1. As shown in the figure, the vagus nerve ends in for nuclei in the brainstem. Two of these contain efferent fibers, the posterior nucleus of the vagus nerve and nucleus ambiguous; and two are related to afferent fibers, the nucleus of the solitary tract (NTS) and spinal trigeminal nucleus.
The vagus nerve serves vital functions such as heart rate control, peristalsis of the gastrointestinal tract, or movement of mouth muscles that affect speech. Also, it serves an important role in neurological processes and cognitive functions (L. Colzato & Beste, 2020). The vagal tone (i.e. the correct function of the vagus nerve) has been found to decline with age, which results in impaired cognition, dementia, and risk to develop central nervous system diseases (Gao et al., 2013). VNS is a proven therapeutic tool to improve and restore the vagal tone (Bonaz et al., 2016).
As mentioned earlier, the vagus nerve can be stimulated by applying mild pulses of external electrical energy to it. The stimulation technique that has gained the most interest is tVNS, due to its simplicity and non-invasive nature. In tVNS, the electrical impulses stimulate the afferent auricular branch of the vagus nerve, and the signal is transferred into the nuclei in the brainstem. Here, it has been suggested that the locus coeruleus (LC) and NST are excited, which, in turn, propagate the signal to the hippocampus and some regions of the cerebral cortex (Shiozawa et al., 2014). This stimulation results in increased segregation of neurotransmitters gamma-aminobutyric acid (GABA) and noradrenaline (NA), which are related to a number of cognitive effects (L. Colzato & Beste, 2020).
The noradrenergic system, of which the nucleus is the LC, is related to sleep/arousal cycles. It regulates the sympathetic discharge and inhibits the parasympathetic tone in arousal responses. According to the Adaptive Gain theory, high NA segregation results in an increased focus on the current task and avoidance of exploring other options (Aston-Jones & Cohen, 2005). On the other hand, GABA is the main inhibitory neurotransmitter of the brain and is known as the natural calming agent of the brain. The GABAergic system is associated with memory and learning, and, similar to NA, it is related to focus and inhibition of other options (Beste et al., 2016).
tVNS is applied using a simple device comprised of two main components: a stimulation unit that contains the pulse generator and battery, and an earplug electrode. The electrode is placed on the left outer ear, specifically, the cymba conchae, the ear canal, or the tragus have been shown to activate the vagus nerve (Yakunina et al., 2017). The parts of the outer ear and an example device are shown in Figure 2.
Figure 2. Parts of the outer ear, and connecting electrode clip to the tragus
Once the electrode is placed, the device sends mild, periodic electrical signals to the electrode. The intensity of the signals is controlled by the user, and must be adjusted to the point in which slight tingling is perceived in the ear. These signals excite the auricular branch of the vagus nerve, which, in turn, stimulates the secretion of GABA and NA in the brainstem.
Many parameters have to be considered when applying tVNS, which might have an impact on the results of the stimulation: signal frequency, current intensity, pulse width, on-off cycles, and duration of stimulation. Commercial stimulation devices usually come with fixed values: 25 Hz frequency, current intensity up to 3 mA, 0.25 ms pulse width, and 30 s on-off cycles. The relation of frequency, intensity, and pulse width with LC activation has been shown to be linear and positive (Hulsey et al., 2017). However, LC activation is believed to have an inverted U-shape relation with cognitive performance, with several studies showing better performance with intermediate parameter values (L. Colzato & Beste, 2020).
The effectiveness, good tolerability, and safety of tVNS are well established through several scientific studies (von Wrede & Surges, 2021). In fact, tVNS devices have received the European CE certification indicating compliance with health and safety requirements (Kreuzer et al., 2012). However, it should be pointed out that side effects have been reported in some cases, even if these are very few and mild. The most common side effects are the sensation of tingling and pain in the stimulation site and slight irritation of the skin under the electrode. Other more severe side effects have been reported by less than 1% of participants, for instance, nausea, headache, or heart palpitations (Redgrave et al., 2018). However, at the present, these have not been studied thoroughly, and the relation with the application parameters is unknown.
Even if tVNS was originally developed as a therapeutic treatment for diseases, in recent years several scientific studies have revealed that it can benefit healthy individuals by enhancing cognitive function (Ridgewell et al., 2021). The improved cognition is a result of the changes in the activity of the noradrenergic and GABAergic systems of the brain. The studies suggest that tVNS can improve health and wellbeing by enhancing cognitive control (i.e. the ability to maintain focus), regulating emotions and recognizing the emotions of others more accurately, and improving language processing and memory.
Cognitive control, also known as executive function, is the process through which the central nervous system regulates behavior to achieve a goal. Its main goal is to restrain stimuli that are irrelevant to the goal by inhibiting response and attention. Cognitive control can be evaluated by forced-choice reaction time tasks. In these tasks, participants are presented with different stimuli, and they have to selectively attend and respond to one while ignoring the distracting stimuli. Examples of such tests are the Flanker, Simon, and Stroop tasks.
Several studies have seen improvements in cognitive control with tVNS. Participants subjected to tVNS showed improved response times, which is the reaction time to stop a process and simultaneously change to another one (Sellaro et al., 2015). Crucially, they also showed increased post-error slowing (i.e. slowing a process after errors or negative feedback), which is linked to the activity of the noradrenergic system. Other recent studies have shown that tVNS improves performance in other tests and tasks related to cognitive control, such as reversal trials, Stop-Change paradigms, and response inhibition while multitasking (Jongkees et al., 2018; Keute et al., 2020; Sun et al., 2021).
Emotion recognition and regulation is a subtype of cognition. The evolutionary perspective suggests that the vagus nerve plays a key role in our social engagement with the environment, and thus, it is connected to the ability to regulate emotion (Maraver et al., 2020).
The capacity to regulate and recognize emotions in others has been the focus of some recent tVNS studies. Colzato et al. (2017) performed a Mind in the Eyes test and found that emotion recognition and regulation were enhanced under tVNS for relatively easy tasks. Maraver et al. (2020) used the Rapid Serial Visual Presentation task, and found that tVNS enhanced the perception of gaze direction and emotions. In a very recent study, De Smet et al. (2021) examined the cognition reappraisal process to evaluate emotion regulation, a test that shows subjects emotional events and evaluates the ability to reappraise the meaning of such events and restrain emotional response. The authors concluded that tVNS enhanced significantly the emotion regulation capacity.
tVNS is also involved in the language processing mechanisms of the brain and affects both categorical memory flexibility and word recognition and retrieval.
In a study by Colzato et al. (2018), the fluency of healthy participants in divergent and convergent thinking tasks was significantly improved under tVNS. The categorical memory flexibility, which refers to the ability of thinking of nouns of more varied categories, was also enhanced. Studies about word recognition memory are not as conclusive as the ones on categorical flexibility. An experiment involving word recognition memory tasks did not find any improvements in delayed recognition and immediate recall using tVNS (Mertens et al., 2020). A recent study on word retention with a wider amplitude found improved performance under tVNS, but only in phonologically similar words (Kaan et al., 2021).
Clinical research in epileptic patients suggests that the vagus nerve is involved in processes related to associative and recognition memory. So, several authors have evaluated the potential for memory enhancement of tVNS in healthy individuals.
In a study with elderly individuals, it was found that tVNS improved the performance in a task involving face-name associative memory (Jacobs et al., 2015). In a recent study using a single-blind, randomized, between-subject design, Giraudier et al. (2020) found that tVNS improved the recollection memory of healthy individuals.
tVNS was originally developed as an alternative non-invasive method to traditional VNS for the treatment of drug-resistant epilepsy and depression. As such, there are numerous scientific studies that prove the efficacy of tVNS as an alternative and/or supplementary therapeutic method for these diseases. Recently published reviews show the potential of tVNS in such treatments (Guerriero et al., 2021; Liu et al., 2020; von Wrede & Surges, 2021; Wu et al., 2020).
In addition, tVNS has shown potential as a treatment for myriad diseases and disorders, including alcoholism (Konjusha et al., 2022), obesity and eating disorders (Alicart et al., 2021), chronic pain and migraines (Straube & Eren, 2021), attention-deficit/hyperactivity disorder (Zaehle & Krauel, 2021), tinnitus (Yakunina & Nam, 2021), insomnia (Jiao et al., 2020), and cardiovascular diseases (Chen et al., 2020).
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