Investigating the role of the vagus nerve on risk-taking behavior

Recent studies show the relevance of the gut-brain axis in important cognitive
processes, including mood, stress responses and decision-making. For example,
probiotics interventions can affect risk-taking behavior both in rodents
(Chumney & Robinson, 2006) and humans (Dantas et al., 2022). These findings are
quite relevant for a better understanding of risk-taking behavior since they
indicate the involvement of networks beyond the central nervous system (CNS)
underlying this type of behavior.
Nevertheless, although the effects of manipulations in the enteric nervous
system (ENS) on the central nervous system (CNS) can be observed both via
neuroimaging techniques and behavioral responses, the communication between the
ENS and CNS is yet to be fully understood. Different pathways are involved in
this bilateral communication, namely a biochemical pathway (via
neurotransmitters), a neurological pathway (mainly via the vagus nerve), and an
immunological pathway (including different components of the immunological
system) (Surowka et al., 2015). Therefore, it
is still unclear how the probiotics manipulation can affect brain activity and
consequently behavior.
The vagus nerve is the main neuronal pathway between the ENS and the CNS
(Dinan, Stanton, & Cryan, 2013). The importance of the vagus nerve in the
gut-brain axis was tested in different studies with animal models. In these
studies, animals that received probiotics showed specific behavioral and
cognitive changes that seem to be mediated by the vagus nerve (Breit,
Kupferberg, Rogler, & Hasler, 2018a). Studies show that these changes were no
longer present (or were at least reduced) if the vagus nerve was interrupted
via a vagotomy (Bonaz, Bazin, & Pellissier, 2018; Tillisch et al., 2013). Vagus
nerve impairment also affects the concentration of serotonin, NE, and dopamine
in the CNS (Breit et al., 2018a) as a consequence of affected communication
between ENS and CNS. Simply impairing the vagus nerve is not possible in
humans. However, it is possible to simulate a nervous stimulus from the ENS by
stimulating the auricular branch of the vagus nerve, using non-invasive vagus
nerve stimulation (nVNS). Therefore, we propose a study using nVNS to directly
stimulate the vagus nerve, simulating a neuronal stimulus from the ENS to the
CNS.
Our hypothesis is that this intervention will generate results similar to the
ones obtained using a probiotics manipulation to affect the gut-brain axis.

Primary Objective: Investigate the effects of nVNS on risk-taking behavior
Secondary Objective(s): Compare observed effect with the effects observed after
probiotics interventions using the same task (Chumney et al., 2006; Dantas et
al., 2022). These findings could help clarifying the role of the vagus nerve in
the GBA.

This study includes two sessions of 1 hour each. In each session participants
will
receive non-invasive vagus nerve stimulation (nVNS) in either active or sham
condition. During the sessions participants will answer a series of
questionnaires to control for factors such as self-control, arousal, and time
preferences. After that, the stimulation apparatus will be adjusted to the
sensitivity level indicated by the participant, guaranteeing maximum comfort
and safety. Afterwards the stimulation will start, with a maximum duration of
30 minutes. During which, the participant will perform a computerized task to
estimate their risk-taking behavior. Figure 1 presents a flowchart with the
experimental design in detail.
The same procedure will be used in session 2, which should take place
approximately
1 week after the first session.

1. Investigational product/treatment
MAXTENS 2000 TENS (formerly known as PROSTIM 2000) (MedCat B.V., Klazienaveen,
The Netherlands) used for non-invasive vagus nerve stimulation (nVNS) according
to the procedures of Jacobs and colleagues (2015).

2. Name and description of investigational product(s)
VNS can be stimulated non-invasively using different techniques. Following the
protocol approved by the Ethical Review Board from the Faculty of Psychology
(ERCPN) (protocol 02_07_2013) we will use a general transcutaneous electric
nerve stimulation (TENS) device named MAXTENS 2000 TENS (formerly known as
PROSTIM 2000) unit (MedCat B.V., Klazienaveen, The Netherlands) (Jacobs et
al., 2015).
The TENS stimulator used allows a maximum pulse amplitude of 80 mA, pulse width
from 50 to 250 µs, rate from 1Hz to 150 Hz, and symmetrical bi-phasic
rectangular and monophasic square pulse wave forms. All parameters are
adjustable. The stimulation might be delivered in continuous fashion of as
bursts with intervals that go from 10 to 90 minutes. The equipment might be
seen in Figure 2.A.
The equipment will be used for nVNS by using small intra-auricular electrodes,
Figure 2.B, stimulating the auricular branch of the vagus nerve, which is a
non-invasive form of transcutaneous electric stimulation. The stimulation is
delivered through these electrodes over the cymba conchae, Figure 2.C, which is
exclusively innervated by the vagus nerve (Badran et al., 2018). The device
received the European clearance (CE mark) in 2014 (certificates available in
http://www.protechsite.com/eng/cer/cer03.html ).

Thus far, only one study systematically reviewed the side effects of the
different nVNS methods, reporting their safety and tolerability (Redgrave et
al., 2018). The authors reviewed 51 studies with 1322 participants, including
patients with epilepsy (5 studies), migraine or cluster headache (15 studies),
tinnitus (2 studies) and depression (4 studies). The stimulation site of
included studies varied between concha (14 studies), tragus (11 studies) and
CVN (13 studies). Of the 1322 participants, only 35 participants dropped out
due to side effects.
The most reported side effect (18%) was local discomfort and mild skin
irritation that disappeared shortly after the stimulation stopped. Other
reported side effects were paresthesia (16.7%), headache (3.3%), dizziness
(1.4%,), facial droop (1.3%,), nausea (1.1%) and nasopharyngitis (1.6%).
Cardiac side effects such as palpitations, arrhythmia, hypotension, and
bradycardia were reported by 7 out of 1322 participants (Redgrave et al.,
2018). Nevertheless, these side effects were observed in studies using nVNS
over the neck and not over the auricular branch of the vagus nerve (Redgrave et
al., 2018). Serious adverse effects after nVNS were reported in only one of the
51 studies reviewed by Redgrave et al. (2018). However, such study used as
subjects patients with drug-resistant epilepsy (n=37). Considering that our
participant pool includes only healthy subjects, SAEs are extremely unlikely.
Considering the extensive exclusion criteria, the screening procedure, constant
monitoring of the subjects we do not expect (S)AE side effects.
The consent discussion starts sufficiently in advance of the initiation of
study-related proce-dures to allow potential subjects time to reflect on the
potential benefits and risks and possible discomforts. Participants are
informed about our standard studies when they are screened (usually days before
inclusion) and the risk associated with participation in this study can be
regarded as minimal.
The results of this study will provide us with better insight into the
mechanisms of the gut-brain axis in decision-making under risk by exploring the
role of the vagus nerve in this mechanism.