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Gizem ZORLU GÖRGÜLÜGİLa,
Ali Veysel ÖZDENb
aAntalya Atatürk State Hospital,
Clinic of Internal Medicine,
Antalya, Türkiye
bBahçeşehir University
Faculty of Health Sciences,
Department of Physiotherapy and
Rehabilitation,
İstanbul, Türkiye
Correspondence/Yaz ışma Adresi:
Gizem ZORLU GÖRGÜLÜGİL
Antalya Atatürk State Hospital,
Clinic of Internal Medicine,
Antalya, Türkiye
gizemzorlug@gmail.com
TO CITE THIS ARTICLE:
Zorlu Görgülügil G, Özden AV. Personalized
auricular non-invasive vagus nerve stimula-
tion system for inflammatory bowel disease
treatment. In: Alptekin HK, ed. Vagus Nerve
Stimulation. 1st ed. Ankara: Türkiye Klinikleri;
2024. p.45-52.
Personalized Auricular Non-invasive
Vagus Nerve Stimulation System for
Inflammatory Bowel Disease Treatment
İnflamatuar Bağırsak Hastalığı Tedavisinde
Kişiselleştirilmiş Non-invaziv Auriküler
Vagus Sinir Uyarım Sistemi
ABS TRACT Inflammatory bowel disease (IBD) is a chronic relapsing clinic condition whose cure could
be very difficult even with new treatments. Although tremendous changes have occured in IBD treatment;
there is an unmet need for a low-cost, easy-to-access treatment associated with low side effects. Possi-
ble dysfunction of interaction between the microbiome-gut-brain axis and autonomic nervous system; ex-
pecially vagus nerve dysfunction can be targeted for a new therapy. Given this, vagus nerve stimulation
(VNS) camoes to the fore. Using present literature, we reviewed pathophysiology of IBD and anti in-
flammatory effect of VNS and the current aim of this review is to provide a comprehensive understand-
ing of the effect of VNS on gut inflammation and the potential of personalized auricular VNS on IBD
management. In the field of precision medicine these days, when digital transformation in health comes
to the fore, personalized auricular VNS which uses machine learning algortims may be an complemen-
tary treatment of IBD.
Keywords: Autonomic nervous system; complementary medicine; inflammatory bowel disease;
vagus nerve stimulation
ÖZET İnflamatuar bağırsak hastalığı (İBH), yeni tedavilere rağmen tedavisi çok zor olabilen kronik,
tekrarlayıcı bir klinik durumdur. İBH tedavisindeki büyük değişiklikler gelişse de; yan etkisi az, düşük
maliyetli ve kolay erişilebilen bir tedavi ihtiyacı devam etmektedir. Mikrobiyota-bağırsak-beyin aksı ile
otonom sinir sistemi arasındaki disfonksiyon; özelliklerde vagus sinir fonksiyonundaki bozukluk yeni te-
davilerin hedefi olabilir. Bunlar göz önünde bulundurulduğunda vagus sinir uyarımı (VSS) ön plana çık-
maktadır. Mevcut literatürü kullanarak, İBH’nin patofizyolojisi ve VSS’nin antiinflamatuar etkisini
derledik ve VSS’nin bağırsak inflamasyonu üzerindeki etkisinin ve İBH yönetiminde kişiselleştirilmiş
auriküler VSS’nin potansiyelinin anlaşılmasını sağlamayı amaçladık. Sağlıkta dijital dönüşümün ön
plana çıktığı günümüzde, makine öğrenmesi algoritmalarını kullanarak kişiselleştirilmiş auriküler VSS,
İBH’nin tamamlayıcı bir tedavisi olabilir.
Anah tar Ke li me ler: Otonom sinir sistemi; tamamlayıcı tıp; inflamatuar bağırsak hastalığı;
vagus sinir stimülasyonu
45
Inflammatory bowel disease (IBD) of which the most common types are ulcerative
colitis (UC) and Crohn’s Disese (CD) is a chronic relapsing disease that effects
mostly intestines but extraintestinal presentation can be seen as well. IBD is a mul-
tifactorial disease in which environmental, genetic and immunological factors are in-
volved together in pathogenesis. Furthermore, it has been shown that dysregulated
immüne response to intestinal microbiota contribute to pathogenesis, resulting in per-
sistent gut inflammation. Both two types of IBD share common pathological factors but
clinical presentation varies depending on disease and affected part of the intestine. CD
is characterized with segmental deep gut wall inflammation throughout the gastroin-
testinal tract but UC involves the recto-colon. Both disease have extraintestinal in-
volvement and the disease progress with recovery and flare
periods which leads to chronic recurrent ulceration of the
bowels.1 IBD have a significant impact on the quality of
life of the patients.
IBD has become a global disease with the rising num-
ber of patients worldwide. Formerly IBD is regarded as a
disease of westernized nations but its prevalence and inci-
dence increase all over the world due to cultural change es-
pecially for diet in the world. Highest reported prevalence
was still in Europe and North America but since 1990 its
incidence has been rising in newly industrialized countries.2
IBD is a chronic relapsing remitting disease of which
full recovery cannot be achieved with current therapies.
IBD management focuses on suppression of gut inflam-
mation and adequate symptom control. Traditional treat-
ments include corticosteroids, mesalamine, thiopurine and
methotrexate. A comprehensive understanding of the in-
flammatory pathways that play a role in disease pathogen-
esis transformed IBD management. Over the last two
decades, therapies that focus on basic molecular pathways
that serve as control points were developed. Inhibitors of
anti-tumor necrosis factor (AntiTNF-α) are the first bio-
logic agents followed by more specific agents that targets
only intestinal inflammation like anti integrin therapies and
anti IL 12/23. Janus kinase (JAK) inhibitors and sphingo-
sine-1 phosphate (SIP) receptor modulators are small mol-
ecule agents emerging for treatment of IBD.3
Although tremendous changes have occurred in the
management of IBD, there are still gaps regarding optimal
therapy, providing quality of life and preventing compli-
cations associated with disease itself drugs used in IBD
management. Many IBD patients cannot reach biological
agents even if their efficacy and safety proven because of
various reason including insurance coverage or high cost of
treatments. IBD is a continual debilitating ailment because
of restricted treatment benefit. Lots of IBD patients are
considered primarily nonresponders or they develop re-
sistance to biological agents during the course of treatment.
Serious side effects of these agents are the other limitation
of IBD management. There is an unmet want for brand
spanking new treatment options, that gives a rise for im-
proving new strategies about disease outcome and patient’s
quality of life.
Autonomic nervous system (ANS) comprises two
separate systems, sympathetic and parasympathetic which
work together in a dynamic balance. The state of dysregu-
lation refers to a condition that one of these two systems
dominates the other on efor extented periods has been pro-
posed to be a risk factor for chronic autoimmun disease
like romatoid artritis.4 It has been shown that vagus nerve
stimulation in patients with epilepsy reduces the produc-
tion of TNF, IL1ß, and IL6 in the peripheral blood. Based
on this, the study conducted in patients with rheumaoid
arthritis, an autoimmune disease, showed that vagus nerve
stimulation performed 4 times a da inhibits the production
of TNF and it was mentioned that it could reduce inflam-
mation. These findings emphasize that vagus nerve stimu-
lation with bioelectronic devices has the potential to be
used in the treatment of rheumatoid arthritis and other au-
toimmune disease.5 Vagus nerve (VN) is the longest cranial
nerve in the body and the main component of the parasym-
pathetic system. Accumulating data shows that vagus nerve
stimulation (VNS) has an anti-inflammatory effect on var-
ious systems hence it has a potential as an alternative treat-
ment for disease that is characterized with excessive
inflammation.6
In the age of digital transformation in health, the im-
portance given to precision medicine is increasing. With
the developments in health Technologies and using bio-
electronic devices, patients’ data such as age, race, weight,
comorbidities and laboratory values can be evaluated with
algoetims and comparisons can be made before and after
therapy, amd improvements can be made in personalized
auricular vagus nerve stimulation. The objective of this
special report is to provide an overview of the potential of
personalized auricular non-invasive VNS which uses ma-
chine learning algoritms for management IBD.
PATHOPHYSIOLOGY OF
INFLAMMATORY BOWEL DISEASE
Exact mechanism behind chronic gut inflammation is not
fully known but substantial progress has been achieved in
the field of IBD pathogenesis in the last decades. Interac-
tions between anti-inflammatory and proinflammatory im-
mune cells, intestinal microbiota, environmental factors
and genetic susceptibility are key factors of IBD patho-
genesis.1 Furthermore, accumulating data reported that
ANS is involved in this pathogenesis. Impaired brain-gut-
axis is shown as one of the causes of the IBD.
Intestinal epithelium (IE) functions as a primary cel-
lular barrier to the gut luminal contents. Although it seems
that the primary function of IE is nutrient absorption, it also
responds to immune cells and gut microbiota. Intolerance
to gut luminal content like gut microbiome or food proteins
is achieved with integrity of IE. Hence dysfunction of IE
like decrease in mucus secretion and antimicrobial protein
or disruption of integrity of IE lead to activate excessive
immüne response to gut luminal content.7
Gizem Zorlu Görgülügil, et al. Personalized Auricular Non-invasive Vagus Nerve Stimulation System for Inflammatory Bowel Disease Treatment
46
Human gut is colonized at birth with various mi-
croorganisms like virüs, bacteria and fungus. This struc-
ture is called microbiome, it has a commersal relationship
with human organism and is neccessary for homeostasis.
Disruption in childhood improvement hava an effect on
the formation of the microbial community structure, dys-
biosis, and/or impared immune response and consequently
cause various problems.8 The gut microbiota can be al-
tered by diet, smoking, alcohol consumption, probiotics
or prebiotics; so it is associated with environmental fac-
tors.9 Altered host immune response to normal intestinal
microbiota or dysbiosis of microbiota are key drivers of
IBD pathogenesis. Both two type sof IBD (UC and Crohn)
are linked to a decrease in the total number of microor-
ganisms, diversity, and richness as well in the gastroin-
testinal tract.1
Hallmark of IBD is chronic inflammation with flares
of disease involving innate as well as adaptive immunity
with an abundance of both neutrophils and T cells in the
inflammatory lesions. Macrophages play a primary func-
tion withation of non-caseous epithelioid granulomas in the
intestinal mucosa. Activated macrophages produce cy-
tokines, including TNF-α and interleukins (IL-6, IL-8, IL-
12, IL-23).10 Antigen bearing dendritic cells present
antigens to naive T cells. T cells differentiate into type 1
helper T (Th1) and type 17 helper T (Th17) cells. Studşes
show increased oligoclonal T cells and reduced B cells,
which also shown at histology; an intestinal graft versus
host appearance, epithelial cell apoptosis, eosinophilia and
neutrophilic infiltrates and villous atrophy in the small
bowel. Defects in B-cellular improvement lead to an ab-
sence of circulating mature B cells and antibody manufac-
turing that have been related to IBD phenotype.8
Brain gut axis includes bidirectional communication
of neuronal, hormonal and metabolic signals. Visceral in-
formation is carried by the ANS to the brain stem and then
transferred to the higher centers in the brain. ANS related
brain regions constitute the central autonomic network and
establish homeostasis. Underlying this connection is the
gut microbiota, which may be viewed as an external envi-
ronment within the body. Its metabolites have an impact
on the vagus nerve.11,12 Several animal and observational
studies reported compelling evidence of the role of the
brain-gut axis in IBD pathogenesis. One study reported that
CD patients have decreased parasympathetic tone when
compared with healthy individuals.13 This aspect has been
thought as a potential target for management of IBD via
therapeutic intervention to neural system to alter the
inflammation in gut.
ANTI-INFLAMMATORY EFFECT OF
VAGUS NERVE STIMULATION
ANS is a key regulator of immunity and it is related to the
production and control of inflammation. ANS has sympa-
thetic and parasympathetic subdivision with main nerve
being vagus, both play a crucial role in the crosstalk with
the immune system. The cholinergic anti-inflammatory
pathway has been implicated as an important mechanism to
regulate inflammation of targeted tissue. This pathway in-
cludes the acetylcholine (ACh) release and α7 nicotinic
acetylcholine receptor (α7nAChR) activation in the spleen
is often cited as the mechanism underlying the effect of
VNS on inflammation.14 The relationship of the VN with
the microbiota, enteric nervous system and intestinal lym-
phoid tissues are other possible ways of role of VN on in-
flammation. Vagal efferents can affect immune responses
in the gut via the enteric nervous system and can trigger
immunomodulatory responses via the release of neuropep-
tides and other signals at the target organs.15
Vagal efferent fibers interact with neuronal nitric
oxide synthase (nNOS), vasoactive intestinal peptide (VIP)
and choline acetyltransferase (ChAT) positive myenteric
neurons, with nerve endings in close proximity to resident
macrophages carrying α7nAChR. They speculated that the
cholinergic anti-inflammatory input to the intestine is me-
diated and thereby amplified by the ENS.16 Matteoil, et al.
Investigated the neural pathway and the cells mediating the
anti-inflammatory effect of VNS in the gut. They showed
that the anti-inflammatory effect of the VNS in the intes-
tine is independent of the spleen and T cells. Instead, the
vagus nerve interacts with cholinergic myenteric neurons
in close contact with the muscular is macrophages. In the
light of this information the study supports the role of the
vagus nerve in the anti-inflammatory pathway of the in-
testine.17
VNS was shown to reduce local and systemic in-
flammation in animal models. Ghia et al showed in their
study that myeloperoxidase activity, levels of serum amy-
loid-P, and colonic tissue levels of interleukin (IL)-1beta,
IL-6, and tumor necrosis factor-alpha were increased sig-
nificantly in vagotomized mice.18 In addition to its anti-in-
flammatory properties, VNS is useful in reversing
dysbiosis, which plays a part in the pathophysiology of
IBD. Animal research has provided compelling evidence
that gut microbes may activate the VN, and that this acti-
vation is essential for mediating effects on the brain. Even
in the absence of overt inflammation, the vagus seems to be
able to distinguish between potentially pathogenic and non-
pathogenic germs. Afferent signals to the brain, which ac-
Gizem Zorlu Görgülügil, et al. Personalized Auricular Non-invasive Vagus Nerve Stimulation System for Inflammatory Bowel Disease Treatment
47
tivate an efferent response and release mediators like ACh
that, through an interaction with immune cells, decrease
inflammation, can be triggered by specific vagal signals
from the gut.19
The major pathway for bidirectional communication
between the gut microbiota and the brain is the VN, which
also elongates the mucosa of the gut. The nucleus tractus
solitarius (NTS) of the medulla in the central nervous sys-
tem (CNS) receives afferents from the parasympathetic
vagal nerves. A reciprocal effect of emotional states on
gut function may be explained by the NTS’s ability to syn-
chronize signals from the gut with cognitive and behav-
ioral activities through connections with the prefrontal
cortex via the amygdala, hippocampus, hypothalamus, and
locus coeruleus. 80% of the neurons in VN are afferent,
and the remaining 20% are efferent, creating an informa-
tion highway between the brain and the gut. Inflammation
is a necessary reaction to tissue damage, but if it is not ap-
propriately controlled, it can lead to inflammatory dis-
eases. Research suggests that homeostatic brain reflexes
control both the initiation and resolution phases of in-
flammation.20
Vagal afferent signals have the ability to specifically
encode information regarding inflammation.21 Egerod et
al. have provided a thorough explanation of the sensing
processes in vagal afferents that are dependent on G pro-
tein-coupled receptors, as well as the potential co-interac-
tion of important receptors with gut-derived chemicals that
are engaged in gut-brain communication.22 The neuroen-
docrine regulation of the inflammatory response can be
modulated by an increase in vagal afferent activity.23
The ANS plays an important role in sensing luminal
contents in the gut by way of hard-wired connections and
chemical messengers, such as cholecystokinin (CCK). The
study of Luyer et al. showed that high-fat enteral feeding in
rats stimulated CCK-receptors centrally or peripherally via
the afferent vagus nerve, leading to inhibition of the in-
flammatory response via vagal efferents and nicotinic re-
ceptors. High-fat enteral nutrition is potentially therapeutic
in various inflammatory disorders such as IBD because of
stimulation of the VN.24 Zanden, et al showed that VN ac-
tivity assists in the surveillance of luminal antigen uptake
by inducing a transient increase in epithelial permeability
and augmenting the uptake of luminal bacteria by mucosal
macrophages. Vagal signaling suppresses the inflamma-
tory response while promoting phagocytosis. Acetyl-
choline release and vagal nerve activity cause macrophages
to adopt an inflammatory, anergic, but highly phagocytic
phenotype.25
It seems that vagus nerve stimulation is a useful
method for reducing inflammation. For a better result,
pharmaceutical treatment and electrical nerve stimulation
therapy could be used simultaneously.14
One could argue that the VN and VNS play a crucial
role in the regulation of inflammation. There is no ques-
tion about the vagus nerve’s distribution in the intestine,
its connection to the ENS, and its role as the primary struc-
ture mediating communication between the gut and the
brain, even though its connection to specific organs like
the spleen is still being studied. Consequently, noninva-
sive, primarily afferent VNS appears to be an excellent
place to start, particularly in inflammatory illnesses of the
gastrointestinal tract.
Vagus nerve stimulation has been shown to reduce
cytokine release in inflammatory disease and is empha-
sized to be effective in providing neuromodulation. Its an-
tiinflammatory effect on the interaction of the vagus nerve
with enteric neurons that secrete neuronal nitric oxide syn-
thase, vasoactive intestinal peptide and choline acetyl-
transferase.26 To mention about the abtiinflammatory
effects of vagus nerve stimulation, the inflammatory reflex
or the cholinergic antiinflammatory route are the two ways
in which it reduces inflammation: by its afferents, it acts
on the hypothalamic-pituitary-adrenal axis, or via its ef-
ferents. By intracting with alfa7nicotinic receptors through
acethylcholine, the VN prevents the release of proinflam-
matory cytokines like TNF.27 In one study, a significant de-
crease in the CD activity index was observed in patients
with drug refractory Crohn’s disease who applied vagus
nerve stimulation for 16 weeks.28
VAGUS NERVE STIMULATION IN
MANAGEMENT OF IBD
The anti-inflammatory impact of VN may be advantageous
in IBD patients when the cholinergic anti-inflammatory
route is taken into account, as evidence is mounting.29
When it comes to treating TNF-mediated chronic inflam-
matory diseases, VNS can be an effective treatment route.
VNS was approved by the US Food and Drug Ad-
ministration (FDA) for the treatment of drug-resistant
epilepsy and depression in 1997 and 2005, respectively.
Research on the antiinflammatory effects of vagus therapy
and its potential impacts on autoimmune disease is quite
promising. Studies of vagus nerve stimulation in patients
with epilepsiy have shown a decrease in the production of
TNF, IL1ß and IL6 in the peripheral blood. It could also
been indicated that vagus nerve stimulation in patients with
Gizem Zorlu Görgülügil, et al. Personalized Auricular Non-invasive Vagus Nerve Stimulation System for Inflammatory Bowel Disease Treatment
48
rheumatoid arthritis inhibits the production of TNF and
may reduce inflammation. These results point to the po-
tential use of vagus nerve stimulation with bioelectronic
devices in the treatment of rheumatoid arthritis and other
autoimmune disease.5
As previously indicated, there are drawbacks to the
present IBD treatment strategies, such as medication side
effects or expense, even if novel, promising biological ther-
apies (anti-TNF medicines) have shown promise in treating
30-60% of patients. Studies on animals have shown that
VNS can prevent the stomach and liver from secreting pro-
inflammatory TNF. With currently available technology,
there is a chance to reduce gastrointestinal inflammation
in people with IBD by noninvasively applying transcuta-
neous vagal stimulation. If patients are not responding well
to the already approved medical therapy, this novel strategy
may enable clinicians to deliver a safe, non-pharmacolog-
ical adjuvant therapy.30
Acute cortical activation in low frequency bands is
caused by VNS, and a decrease in alpha power resulting
from VNS is associated with a clinical improvement in
Crohn’s disease. Through afferent vagal fibers, chronic
VNS regulates the anxio-depressive symptomatology
linked to CD. While chronic VNS has been linked to de-
creased alpha activity, VNS mostly enhances delta and
theta activity. Afferent vagal fibers in chronic VNS have
the potential to influence the central autonomic network as
well as the central nervous system. Therefore, it can be hy-
pothesized that VNS uses afferent fibers to treat autonomic
dysfunction.31
The VN interacts with α7nAChR to reduce immune
cell activation through the release of acetylcholine. It is
highly likely that the VN interacts with immune cells in the
gut to raise cholinergic tone, which lowers mucosal in-
flammation and transforms innate immune cells into a
tolerogenic state. Chronic inflammatory illnesses like IBD
may be treated with electrical stimulation of the VN, either
in the neck or the ear. It is important to recognize that the
discovery of the VN’s anti-inflammatory properties repre-
sents a significant advancement with huge therapeutic po-
tential.32 It’s now known that a variety of inflammatory
disorders have decreased vagal tone, and that this could be
a risk factor linked to pathogenesis. Thus, evaluating and
returning vagal tone to normal may be a key treatment ap-
proach.6
Apart from the cholinergic anti-inflammatory path-
way, VNS can also impact the hypothalamic-pituitary-
adrenal axis and cause the adrenal glands to secrete
cortisol. The VN appears to be a promising therapeutic tar-
get not just for inflammatory disorders of the digestive tract
(like IBD), but also for other inflammatory conditions like
RA and others, considering its role as a crucial component
of the ANS in the brain-gut interactions in IBD. Potentially
employed as a non-drug treatment for TNFα-related disor-
ders, VNS is an anti-TNFα therapy. It could be used in con-
junction with conventional treatments or as an alternative
non-drug therapy.33,34
In addition to altering intestinal immunity, flora, and
permeability, stress could be the cause of the ANS to be-
come more sympathetically hyperactive. Immunological
resistance to a threat is reinforced by the sympathetic nerv-
ous system through the induction of a pro-inflammatory
response. So that, an inflammatory process can be facili-
tated by any form of vagal hypotonia, whether or not there
is sympathetic hypertonia. In individuals who are at risk, it
can be presumed that the degree of vagal tone is predictive
of the development of IBD. Vagal hypotonia, which in turn
sustains this inflammatory state, can result from the sys-
temic inflammation seen in inflammatory bowel disease
(IBD) and other chronic inflammatory diseases. The
restoration of vagal activity through any therapy, drug-
based or not, like VNS, may therefore be beneficial for
treating not only IBD but also other chronic non-digestive
inflammatory disorders. VNS can be used in addition to or
as a substitute for biologic medicines in treatment. How-
ever, VNS is cheaper than biologics and has no significant
adverse effects.35
In one study where VNS was applied for a duration of
one year and was well tolerated by Crohn’s disease pa-
tients, a reduction in endoscopic remission, decreasing of
CRP and fecal calprotectin levels was observed.36
Though not usually to an acceptable extent, the ther-
apies currently in use help symptoms and lower inflam-
matory activity. Conducting clinical trials utilizing
electrical VNS for the treatment of CD and other gastroin-
testinal disorders characterized by elevated inflammation is
crucial in order to clarify these new anti-inflammatory
pathways that may have potential therapeutic applica-
tions.37 One study reported the effect of noninvasive VNS
on IBD patients. This randomized study enrolled IBD pa-
tients 10-21 years of with mild to moderate CD and UC
who did not achieve remission on conventional therapy.
The study showed that patients who received VNS had
lower fecal calprotectin levels when compared with the
control group.38
Electrical stimulation is the most commonly used
method but questions about the optimum stimulation sites
(abdominal, cervical, auricular), stimulation techniques (in-
Gizem Zorlu Görgülügil, et al. Personalized Auricular Non-invasive Vagus Nerve Stimulation System for Inflammatory Bowel Disease Treatment
49
vasive or noninvasive) and stimulation parameters (pulse
width, frequency, duration, intensity) are still unan-
swered.39 According to the results of preclinical and out-
standing clinical studies, it is really an exciting time in the
subject area of bioelectronic medical devices. There are
some challenges and opportunities in this area. Fixing po-
tentially contradictory results is also part of it, as are func-
tional circuits in many animal species and organ systems
and a comprehensive comprehension of how electrode de-
sign and simulation settings can be optimally tailored to
activate particular nerves.40
NOVEL METHOD FOR VAGUS STIMULATION:
PERSONALIZED AURICULAR STIMULATION
A fundamental idea in bioelectronic medicine is to use
well-studied homeostatic reflexes to replace or enhance
medication by electrically stimulating particular brain cir-
cuits. The development of closed-loop systems with the
ability to independently modify treatment in response to
physiological measurements pertinent to a disease is part of
the long-term vision. However, most of the devices that are
now available for clinical studies involving humans are
electrical nerve stimulators that require manual program-
ming. Subsequent investigations have shown lower pro-
duction of TNF-α, IL-1β, and IL-6. The anti-inflammatory
mechanism was mediated by ACh produced in response to
vagus nerve stimulation. In the end, peripheral nervous sys-
tem signals will be able to control inflammation.20
It is currently uncertain what the ideal VNS parame-
ters are to effectively relieve inflammation-related symp-
toms by bringing the right fibers into the VN. The shape of
VN affects how fibers react to electrical stimulation. In in-
vasive VNS, nerve fiber responses to electrical impulses
given through a cuff electrode are primarily influenced by
several factors, including nerve diameter (and hence, elec-
trode-fiber distance), fascicle diameter, fascicular organi-
zation, and perineurium thickness.35
The choice of electrical stimulation parameters is cru-
cial for the control of cytokines through the cervical vagus
nerve, and it is possible to enhance some cytokines with
electrical stimulation even in the absence of inflammation.
The identification of specific fiber populations that regulate
the neural regulation of inflammation and the most effec-
tive methods for activating them will be necessary to en-
sure the effectiveness of the selective stimulation
paradigms for both invasive and noninvasive cervical
VNS.41 We speculate that this may be due in part to the di-
rect activation of the vagus efferent fibers by cervical stim-
ulation. To combat this, in the near future, the creation of
bioelectronic devices ought to be combined with ideal
stimulation parameters in order to more effectively treat
particular ailments.42
For IBD patients, personalized auricular VNS may
offer answers to all of the aforementioned issues. For in-
stance, noninvasive devices that stimulate both ears from
the tragus and concha regions may be able to override the
vagus nerve’s selective stimulation. Therefore, surgical
complaints and associated costs are first avoided; the cost
of the electrode and neurostimulator for the invasive form
of VNS is high.35 Second, efferent fibers of the VN are not
immediately activated. The best ear to stimulate while
using auricular VNS is a topic of discussion. Due to its ef-
ferent fiber stimulation properties, invasive cervical VNS
is administered from the left side in order to minimize car-
diac side effects. Thus, auricular VNS is applied to the left
side in a similar manner. That being said, both left and right
ear impulses ultimately travel to the same location; through
the NTS. Because the brainstem receives more sensory
input when both the left and right auricular vagus nerves
are activated simultaneously, the effects of stimulation may
be amplified.43 The literature contains only few studies that
used bilateral auricular VNS.44 It is feasible to determine
whether stimulation should be performed in the left or right
ear by gathering data from each patient and applying arti-
ficial intelligence’s machine learning algorithms.
Machine learning algorithms may be the answer to
overcome the optimization and personalization of stimula-
tion. We believe that with the increasing amount of data,
machine learning algorithms can process the demographic
characteristics of patients and data on their comorbidities,
along with the adjustability of bioelectronic devices like
VNS, to develop customized treatment models for each pa-
tient. In the field of precision medicine these days, when
digital transformation in health comes to the fore, person-
alized auricular VNS which uses machine learning algor-
tims may be an complementary treatment of IBD.
THE PERSONALIZATION PROCESS OF
STIMULATION PARAMETERS
In order to generate optimized and personalized stimula-
tion parameters, machine learning algorithms are required
because there are no predefined and determined current
equations and formulas about it. Current vagus nerve stim-
ulator devices use standard parameters for everyone with-
out personalization and do not include a biofeedback
mechanism about the efficacy of the stimulation. There-
fore, a vagus nerve stimulation with personalized parame-
ters should be implemented in order to increase the
Gizem Zorlu Görgülügil, et al. Personalized Auricular Non-invasive Vagus Nerve Stimulation System for Inflammatory Bowel Disease Treatment
50
effectiveness of the treatment. Thus, constructing a data-
base that includes previous patients’ stimulation parame-
ters and objective/subjective stimulation results is the first
and crucial part of the system. Along with stimulation pa-
rameters, subjective inputs are pre/post-stimulation surveys
related to the condition of the patient. Besides these, ob-
jective parameters are blood test results, heart rate vari-
ability (HRV) measurement via photoplethysmography
method, and other biofeedback mechanisms which give us
insights about the effectiveness of the VNS.45 Upon build-
ing a database with two clusters, representing successful
and unsuccessful stimulation parameters from prior appli-
cations, classifiers will first undergo training to ensure they
are close to the successful parameters and far from the un-
successful values simultaneously. The classification
process will be conducted on every stimulation, and its re-
sults will feedback to the database. The larger feature set
(medical history, age, weight, height, biofeedback data,
etc.) and numerous stimulation which are labeled as suc-
cessful and unsuccessful stimulation parameters will en-
hance the system accuracy that generates optimum,
personalized stimulation parameters for newcomer and ex-
isting patients. Yu, et al. stated that closed loop auricular
VNS continues to emerge as a promising neuromodulation
modality. Closed loop stimulation systems are recom-
mended for auricular vagus nerve stimulation as in other
areas of neuromodulation. In the near future, we may see
EEG and ECG datasets, blood glucose or cytokine levels
being used for biofeedback in patients.46
CONCLUSION
Since auricular VNS does not directly stimulate the effer-
ent fibers and is noninvasive, it can be preferred and eas-
ily applied in the treatment of IBD patients. Machine
learning algorithms can play an important role in increas-
ing the effect while reducing the side effect via optimizing
and customizing the stimulation in the digital age of health-
care. Auricular VNS could provide clinicians the ability to
offer a safe, non-pharmacological adjuvant therapy for pa-
tients who have failed the currently approved medical ther-
apy for IBD patients.
Gizem Zorlu Görgülügil, et al. Personalized Auricular Non-invasive Vagus Nerve Stimulation System for Inflammatory Bowel Disease Treatment
51
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