Emma Quiet

HOW VAGUS NERVE THERAPY

CAN IMPROVE YOUR LIFE
The New Medical Revelations for Building Self
Confidence, Avoiding Anxiety, and Reducing
Depression
©Copyright 2020 All rights reserved.
This document is geared towards providing exact and reliable information with regards to the topic and issue covered. The
publication is sold with the idea that the publisher is not required to render accounting, officially permitted, or otherwise, qualified
services. If advice is necessary, legal or professional, a practiced individual in the profession should be ordered. In no way is it
legal to reproduce, duplicate, or transmit any part of this document in either electronic means or in printed format. Recording of
this publication is strictly prohibited and any storage of this document is not allowed unless with written permission from the
publisher. All rights reserved. The information provided herein is stated to be truthful and consistent, in that any liability, in terms
of inattention or otherwise, by any usage or abuse of any policies, processes, or directions contained within is the solitary and utter
responsibility of the recipient reader. Under no circumstances will any legal responsibility or blame be held against the publisher
for any reparation, damages, or monetary loss due to the information herein, either directly or indirectly. Respective authors own
all copyrights not held by the publisher. The information herein is offered for informational purposes solely, and is universal as so.
The presentation of the information is without contract or any type of guarantee assurance. The trademarks that are used are
without any consent, and the publication of the trademark is without permission or backing by the trademark owner. All
trademarks and brands within this book are for clarifying purposes only and are owned by the owners themselves, not affiliated
with this document.
Disclaimer
This book details the author’s personal experiences with and opinions about
the Vagus nerve. The author is not your healthcare provider.
Except as specifically stated in this book, neither the author or publisher,
nor any authors, contributors, or other representatives will be liable for
damages arising out of or in connection with the use of this book. This is a
comprehensive limitation of liability that applies to all damages of any
kind, including (without limitation) compensatory; direct, indirect or
consequential damages; loss of data, income or profit; loss of or damage to
property and claims of third parties.
You understand that this book is not intended as a substitute for consultation
with a licensed healthcare practitioner, such as your physician. Before you
begin any healthcare program, or change your lifestyle in any way, you will
consult your physician or another licensed healthcare practitioner to ensure
that you are in good health and that the examples contained in this book
will not harm you.
This book provides content related to physical and/or mental health issues.
As such, use of this book implies your acceptance of this disclaimer.
Please consult with your own physician or healthcare specialist regarding
the suggestions and recommendations made in this book.
Errors
Please contact us if you find any errors. While every effort is taken to
ensure the quality and accuracy of this book, spelling, grammar, and other
errors may be missed in the early version of the publication.
We appreciate you contacting us first if you noticed any errors in this book
before taking other action. This allows us to fix these errors quickly before
it negatively impacts the author.
If you find any issues or errors with this book, please contact us and we’ll
correct them as soon as possible.

Errors@wisementorpress.com

Feedback
For any general feedback about the book, please feel free to contact us at
the email address below:

Contact@wisementorpress.com
 TABLE OF CONTENT
Disclaime r
SECTION 1: Introduction
SECTION 2: Overall insight to the central nervous system and vagus nerve
SECTION 3: The crucial role in weight loss
SECTION 4: The gastrointestinal system and particular inflammatory
events
SECTION 5: Regulation of the gastrointestinal system
SECTION 6: The effects on neuropsychiatric disorders
SECTION 7: An optional remedy for post traumatic stress disorder
SECTION 8: Cognitive skills can be improved by proper stimulation
SECTION 9: A healthy respiratory system
SECTION 10: Relax with deep breathing
SECTION 11: The efficient relaxation methods
SECTION 12: Can meditation techniques relieve our stress via vagal
activity?
SECTION 13: Music can modulate our moods
SECTION 14: The remedies for healing damaged vagus nerve
SECTION 15: Implantable and non-implantable devices for vagus nerve
stimulation
SECTION 16: A big heartfelt thanks, dear friends.
Glossary
References
P.S.
 SECTION 1:
INTRODUCTION
Have you ever felt hopeless and unmotivated? Do you feel tired, and does
your head hurt sometimes? You have taken many pills that don’t work
anymore, tried many remedies and methods, and nothing seems to heal you
completely. Nothing seems to get you out of that dark hole that has become
your life. But you are not alone.
There are many out there who, just like you, can’t find a solution in
medicine. Either treatments stop working or they become dependent on pills
and overuse psychotropic drugs, worsening their health without finding
relief to their emotional and physical pain. You might know people going
through this, or you might be the one going through something similar, but
don’t worry. Reading this book is the first step to changing the way you live
your life forever.
Many others have found solace in the information contained in this book,
and now you can join them. It’s never too late to start your healing journey.
This book is a comprehensive look at how most physical and emotional
problems can originate from one source and how you can significantly
improve your health without filling your body with harmful and unhelpful
chemicals.
The human being has twelve pairs of nerves that start in different parts of
your brain. Now, among all that series of nerves, the number ten is, without
a doubt, the most interesting and powerful: the vagus nerve. It is part of the
parasympathetic nervous system, and its function is concrete as well as
interesting.
The vagus nerve helps you to relax, to achieve an adequate state of calm, to
cope with stress and anxiety, and to enjoy a sense of well-being, which can
improve your quality of life. Not everyone is aware of the importance of
this nerve in our body or even knows it exists.
The vagus nerve, which operates well below the level of our consciousness,
is vital to the health of the body. It plays an essential role in calming the
organs after the discharge of adrenaline when responding instinctively to a
dangerous situation. But not all vagus nerves are the same: there are people
who have greater vagal activity, which makes their bodies take less time to
relax after a stressful situation, while others genetically have low vagal
activity.
Not only is it a fundamental element for the proper functioning of the
organism, but it also constitutes the most direct link between the brain and
the intestinal microbiome, essential for immune and anti-inflammatory
functions .
Studies show that a high vagal tone helps our body to regulate blood
glucose levels, reducing the risk of diabetes, stroke, and cardiovascular
disease. A low vagal tone, however, is associated with chronic
inflammation. Inflammation, which is part of the immune system, helps the
body heal after an injury but can damage blood vessels and organs if it lasts
longer than necessary. Chronic inflammation can lead to:

Migraines

Anxiety

Depression

Cancer

Alzheimer’s disease

Heart Disease

Arthritis

Gastrointestinal problems, and many more

Stimulation of the vagus nerve
Vagus nerve stimulation is a palliative treatment modality for refractory
epilepsy. The history of the vagus nerve and its relation to seizures dates
back at least a century. Stimulation of the nerve and its effects on cerebral
activity were first documented by Bailey and Bremmer in 1938, and this
was followed in 1951 by Dell and Olson. Stimulating the vagus nerve to
alleviate illnesses has been done for a long time, but because of the use of
pharmaceutical treatments, it hasn’t been given much importance. In 1952,
Zanchetti et al. used a chemically induced seizure model in cats and found
that the stimulation of the vagus nerve stopped the seizures. The first human
implantation of the vagus nerve stimulator was done by William Bell.
However, some clinical trials and many studies later, its effectiveness in the
treatment of many ailments (including the ones difficult to treat with drugs)
has been tested and confirmed. An example of the clinical trials is the study
of the non-invasive vagus nerve stimulation for the prevention of migraines.
The purpose of this study is to investigate if the use of the gammaCore
Sapphire device reduces the number of migraines preventively. It was not
until 1997 that vagus nerve stimulation was approved by the US FDA
(Food and Drug Administration) as adjunctive therapy for patients above 12
years with partial-onset and medically refractory epilepsy. It has been
reported that mild depressive disorder and treatment-resistant depression
can be treated with vagus nerve stimulation, and it is effective to treat
arthritis that has stopped responding to pharmaceutical treatments. Many
doctors, scientists, and authors have started talking more openly about it, so
this amazing information reaches more people like you, who are in search
of improving their quality of life. In 1883, Corning proposed that vagus
nerve stimulation could decrease heart rate and cerebral blood flow, thereby
controlling seizures. In 1983, Bailey and Bremer demonstrated the direct
effect of vagus stimulation on the central nervous system. Their results
found that repetitive electrical stimulation of the central end of the vagus
nerve of the cat increased amplitude and frequency of the spontaneous
potentials of the orbital surface of the frontal lobes of the cerebral cortex. In
1992, Zabara also investigated vagus stimulation as a potential method to
treat epilepsy.
What you will learn:
Insight to the central nervous system and the vagus nerve

What role the vagus nerve plays in neuropsychiatric disorders

How the vagus nerve modulates inflammatory events and the

gastrointestinal system

Which vagus nerve stimulation is helpful in the treatment of

post-traumatic stress disorder

How to identify if your vagus nerve is damaged and how it

can be healed

What are the most efficient vagus nerve relaxation methods

This book also talks about all the medical advancements done in the study
of using the vagus nerve to treat or heal even the most difficult of
conditions and chronic illnesses with the use of implantable and non-
implantable devices.
It also covers simpler methods and techniques you can easily follow at
home by yourself.
At the end of this book, you will feel rejuvenated with a sense of clarity,
ready to listen to your body and start your healing journey .
I hope How vagus nerve therapy can improve your life: The new medical
revelations for building self confidence, avoiding anxiety, and reducing
depression and the information contained here is as helpful for you as it has
been for us and many others.
What you have read so far is just a starter. There is so much more to learn.
Discovering the vagus nerve will mark a before and after in your life and
how you see things. Keep reading and learn the secrets that have been kept
from you all this time.
For a better understanding of the text, we have added a glossary of the
underlined terms at the end of the book.
In addition, we are preparing a private group on Facebook where you can
share your experiences and solve your doubts. In order to optimize the user
experience, we have decided to create a closed group so that we can better
follow everyone. To apply, write an email to:
Fb.group@wisementorpress.com

In the email, briefly write who you are and why you would like to join the
group.
My team and I look forward to hearing from you!
Ah, one last thing...
As promised on the book’s cover, you will have the opportunity to follow
our video course.
You will find the course at this link:
Https://Emma.wisementorpress.com/Course1

I don't want to anticipate anything, but I'm just telling you that this 12 day
course has the potential to change your life forever!
 SECTION 2: OVERALL
INSIGHT TO THE
CENTRAL NERVOUS
SYSTEM AND VAGUS
NERVE
What is the vagus nerve?
The vagus nerve originates from the medulla oblongata (one of the brain
regions that controls vital processes in our body) in the central nervous
system. The vagus nerve is the 10th cranial nerve in our parasympathetic
nervous system. It is a long nerve that runs from the hypothalamus area of
our brain, chest, diaphragm , and intestines.
The vagus nerve gets the signal from our brain to deliver the impulse to the
heart, stomach, intestine, lungs, and some of the facial muscles. Also, the
vagus nerve gets information from these organs to transmit through the
central nervous system.
The human body is covered by the sympathetic and parasympathetic
nervous system that regulates voluntary and automatic movements. The
vagus nerve is the main component of the parasympathetic nervous system,
which manages a massive range of vital bodily functions, including control
of mental mood, digestion, ventilation rate, immune response, and heart
rate.
85-90% of nerve fibers connect back to the brain through the vagus nerve.
Body-mind connection, gut instinct, the knot in the throat, and the sparkle
of our smile can be listed as roles the vagus nerve plays. We can think of
the vagus nerve as a two-way signaling communication system, helping us
to stay in touch with our sensations and emotions 7 .
General information about vagus nerve in the
nervous system
The nervous vagus, pneumogastric nerve , and tenth cranial nerve (CN X)
are synonyms of the vagus nerve. In the last half century, you most
probably have confronted at least one of these terms. Due to its wide range
of functions, investigation on the vagus nerve has been increased
significantly in recent years. The secret of this nerve is not completely
understood yet, but several scientific studies have been performed to get
more information about the vagus nerve, and they are still ongoing .
In recent years, new therapy approaches are being constructed on vagus
nerve stimulation or regulation. Most of these new methods give inspiration
to health professionals for healing their patients efficiently. Stimulation of
the vagus nerve can be a healing factor for epilepsy and seizures , or cutting
it may relieve a peptic ulcer. There are other techniques that have been
found to manipulate the vagus nerve1 . We will discuss these in the next
chapters.
The nervous system is divided into two main systems: central and
peripheral. Our peripheral nervous system is mainly controlled by two
regulations: autonomic and somatic. These nervous systems are also
responsible for voluntary muscles and involuntary muscles.
The autonomic nervous system controls involuntary muscles, whereas the
somatic nervous system controls voluntary muscles. The majority of these
muscles are under control of the Involuntary muscles that are present in the
walls of the digestive system, blood vessels, bronchi, uterus and bladder.
Involuntary muscles of the heart, respiratory, and digestive systems work
automatically. These operations are triggered by nerves, and the nerves are
stimulated by complex chemical fluids that surround them and other living
cells. The role of the chemical mediators is essential in operating activities
because in addition to giving life to involuntary contractions, they are also
essential in modulating the activity. For example, when we have breakfast
in the morning, the autonomy system works more than the somatic system.
Voluntary muscles only work during mouth movements, even if the
parasympathetic system helps it. After the esophagus receives the food, the
parasympathetic system gets the responsibility. Next, the digestion of food
and drink is completed with involuntary muscle directions. Nobody needs
to initiate his/her stomach salivation, intestinal movement, or bowel
regulation 2 , 3 . All of these ingestion procedures are accomplished without
voluntary directions. We don’t wonder whether the stomach worked or not.
It is an autonomic nervous turn.

The
autonomic nervous system is divided into two groups: sympathetic and
parasympathetic nerves. “Fight or run” activities are controlled by the
sympathetic nervous system while “rest and digest” activities are controlled
by the parasympathetic nervous system .
The vagus nerve is one of the best employees of the parasympathetic
nervous system. It is also known as the longest nerve in the human body
and is the main contributor of the parasympathetic nerves. The other three
parasympathetic cranial nerves are the nervusfacialis, nervusoculomotorius,
and nervusglossopharyngeus.
When we look at the vagus nerve responsibilities, we can see a wide range
of functions, such as the regulation of internal organ functions; digestion,
heart rate, and respiratory rate 32, as well as vasomotor activity. In addition,
reflex actions; coughing, sneezing, swallowing, and vomiting are all vital
occurrences closely linked with the vagus nerve.
The vagus nerve is associated with endocrine, immune, and humoral
contacts, as well as the influence of gut microbiota . Due to vital K vitamin,
which refers to a group of fat-soluble vitamins that plays a role in blood
clothing, bone metabolism, and regulating calcium levels, synthesis being
made by useful bacteria, gut microbiota is very important for human health.
Maintaining gut population in optimum range presents us a happier life. We
will discuss in the next sections how it works regularly.
There are new treatment options for modulating the brain – gut axis, such as
vagus nerve stimulation and meditation techniques. Although advanced
evidence is needed to confirm the effectiveness and safety, these treatments
have been shown to be beneficial in mental conditions. Maybe it seems
strange, at first, but accumulated scientific evidence supports that mental
health is strongly related to gut actions.. Dysbiosis and inflammation of the
gut have been linked to causing several mental illnesses including anxiety
and depression, which are prevalent in society today. The bidirectional link
between the brain, gut, and microbiome has come to the forefront of the
medical research community in the past few years. The growing amount of
evidence substantiating this link indicates it will be a valuable area for
future medical and nutritional practice, and research. This review
demonstrates the importance of a healthy microbiome, particularly the
microbiota, for patients suffering from anxiety and depression, as dysbiosis
and inflammation in the CNS have been linked as potential causes of
mental illness. We want it to work at an optimal rate, and optimum gut
movements are associated with the vagus nerve.
A new term emerged in 1907: “enteric brain”. It has been known for a long
time that nerve fibers exist throughout our stomach and intestines, but
findings support a new term, the enteric brain. Also a group of scientists
assert the enteric nervous system has characteristic rules that govern the
gut; therefore, it is suggested to be a second brain. The ‘second brain’ term
may seem exacerbated, but their hypothesis is strong. Also, we can’t neglect
the vagus nerve’s role in the second brain 4 . All of these new synonyms
may emphasize particular qualifications of nerves in our abdomen 5 .
A group of scientists encourages this nerve greatly. New uses of vagal nerve
stimulation have become possible in part because of research by Kelvin J.
Tracey of the Feinstein Institute for Medical Research and others showing
that the vagus nerve emits chemicals that helps regulate the immune
system. The release of a specific neurotransmitter in the spleen, for
instance, quiets the immune cells involved in inflammation throughout the
body. The findings might be beneficial for disorders beyond ones that are
marked by disturbed electrical signaling, such as autoimmune and
inflammatory conditions. So far the studies of inflammation-related
applications are encouraging. Vagus nerve stimulation devices developed by
SetPoint Medical have been approved as safe in early human trials for
rheumatoid arthritis, which causes painful, disfiguring inflammation of
joints, and for Crohn’s disease, which involves inflammation of the
intestines. But what is the reason for the vagus nerve becoming so popular?
Maybe you think it is a small part of the nervous system. Yes, it is true that
the length of the vagus nerve is less than 0.01 % of the human body’s
nervous system. The human body sometimes gives enormous importance to
its structures. The human body is a complex system with structures ranging
from cells to organ systems and functions ranging from waste removal to
protection and defense. The functions and structures are dedicated to
maintaining a state of health in the body. An organ is a unique anatomic
structure consisting of a group of tissues that work in concert to perform
specific functions. Particular organs can successfully provide vital body
functions; however, some of them need only a minor area to accomplish
their work, without asking for a bigger place from the body while providing
fundamental functions. This situation can be explained as: generous
structures. We can name our vagus nerve as a generous structure because of
its capability to provide more than our expectations.
Imagine how much area the hypothalamus takes up in the brain. The
hypothalamus is a portion of the brain that contains a number of small
nuclei with a variety of functions. It is small but an important area in the
center of the brain. The hypothalamus is located below the thalamus and is
part of the limbic system. All vertebrate brains contain a hypothalamus. In
humans, it is the size of an almond. When the hypothalamus is not working
properly, it can cause problems in the body that lead to a wide range of
disorders. Maintaining hypothalamic health is vital because of this. It is
known that several essential functions are strictly related with the
hypothalamus, such as fever regulation, releasing hormones, controlling
appetite, sexual behavior etc. But it is a fact that the weight of the
hypothalamus is less than 0.2% of our total brain weight and it is located in
a very small area in the brain. To understand the vagus nerve function in our
body, the hypothalamus would be a good example for us: “Small but
efficient, works like an ant” .
The vagus nerve, the longest of the cranial nerves, controls our inner nerve
center in the parasympathetic nervous system. We will discuss its advanced
functions in the next sections6 .
General overlook of vagus nerve function
The vagus nerve is far reaching, extending from the brain into our stomach
and intestines. There are some evolutionary stages of the vagus nerve, and
regulation of nervous system states might be critical for the vagal nervous
based approaches. Sensitive modulation of the nervous system may
adversely impact our body reflex. The somatic nervous system keeps the
body adept and coordinated, both through reflexes and voluntary action.
The somatic nervous system also provides us with reflexes, which are
automatic and do not require input or integration from the brain to perform..
By understanding the workings of our vagus nerve, we may discover its
potential to affect regulation of crucial organs 8 .
When we feel jumpy, anxious, irritable, and panicky, we feel hot. Inversely,
we experience a sense of cold when we are shut down, depressed, and
hopeless. The human body alternates between the two situations, which is
like driving with one foot on the gas and one on the brakes. The vagus
nerve aims to help us feel either relaxed or alarmed, which is needed to
stimulate the appropriate one.
It is commonly known that healthy organ functioning is closely associated
with a healthy body. We can think that vagus nerve regulation is one of the
main contributors to abnormal physiological conditions. Under
physiological conditions, the sympathetic and parasympathetic (vagal)
activities modulating cardiac function undergo a reciprocal regulation,
leading to sympathovagal balance. For example, when the lungs are
infected by bacteria or a virus, other organs cannot tell the lungs: it is just
your business; combat with the infection by yourself. Inversely, the whole
body takes an alert position to help the lungs. Maybe the heart will increase
its rate, the stomach and bowels regulate their movement, and the brain
decides to fever if needed. The vagus nerve plays a role in these regulations
to preserve health.
The connection between health and trauma is complex, not surprisingly
because there is still a lot of knowledge waiting to be discovered about our
body. The vagus nerve, however, is taking center stage as a potential "off
switch" for inflammation related diseases such as epilepsy, rheumatoid
arthritis, and inflammatory bowel syndrome. One’s mental health can have
a significant influence on the vagus nerve. So it is no surprise that the vagus
nerve regulation can be important for responding effectively to the
emotional and physiological symptoms of depression, anxiety, and PTSD .
There is another field where you can confront the vagus nerve: Yoga, which
can modulate the mood via deep breathing. It sounds mystic. And in the
next few years, we may see the vagus nerve as an emerging key component
in the science of how yoga works 9 .
The great news is that stimulation of the vagus nerve can be evoked by
breathing, certainly ventilation. There are two ways to activate the
parasympathetic nervous system to convince your mind that there is no
more danger or to stop the biological stress response so that it is no longer
in a fight-to-flight mode. What is important to us here is that the vagus
nerve stimulation would communicate both the messages, since it is
responsible for the parasympathetic messaging both from brain to the body
and from the body to the brain. You can not directly or consciously
stimulate your vagus nerve. But you can indirectly stimulate your vagus
nerve by getting yourself into the rest-to-digest mode because this nerve
gets activated during the sympathetic response. The parts of the body the
vagus nerve branches out to are the throat, lungs, heart and abdominal
organs. You cannot consciously control your heart, kidneys or your small
intestine, but can control the depth of your breathing and the muscles of
your larynx which the branches of the vagus nerve also happen to innervate.
It is not surprising that the most commonly suggested technique for
parasympathetic activation is deep diaphragmatic breathing. It makes sense
that -sympathetic response leads to short fast breathing bordering on
hyperventilation and parasympathetic activation leads to deep relaxed
breathing. Every time you exhale you activate the
parasympathetic response ( and the heart rate slows down a bit, vagus nerve
is active ). Deep breathing improves heart rate variability, which is the
measurement of variations within beat-to-beat intervals. Taking a deep
breath, through conscious breathing and expanding the diaphragm , turns on
our parasympathetic nervous system, the stress hormone regulation and
related body functions, how it works and the mechanism of action10 . All of
these will be explained and discussed in this book (section 10).
Key Points in one page
Central and peripheral nervous systems are the 2 main
components of the human body’s nervous system. The vagus
nerve is one substantial component of the peripheral nerve
network that is dominantly under control of the autonomic
nerves.
The vagus nerve, also known as the 10th cranial nerve, runs
from the hypothalamus area of our brain, facial area, lungs,
and diaphragm to our intestines in our parasympathetic
nervous system. The vagus nerve is the main contributor of the
parasympathetic nervous system. The most important function
of the vagus nerve is afferent, bringing information of the
inner organs, such as gut, liver, heart, and lungs to the brain.
Most organs receive parasympathetic efferents through the
vagus nerve and sympathetic efferents through the splanchnic
nerves.
 SECTION 3: THE CRUCIAL
ROLE IN WEIGHT LOSS
Why the vagus nerve is argued to be a new field of
medicine
In the last century, thousands of drugs have been discovered for
miscellaneous disorders. However, we still have not succeeded in finding a
radical remedy for most diseases, such as epilepsy, Alzheimer’s disease,
major depression, and anxiety. A radical remedy represents cleaning the
root of disease. Unfortunately, most diseases can be treated only palliative
with synthetic drugs. For example, about one-third of patients with epilepsy
don't fully respond to anti-seizure drugs. Vagus nerve stimulation can be a
hopeful option to reduce the frequency of seizures . Individuals who haven't
achieved control of their seizures with medications can be guided to vagus
nerve stimulation. In addition, vagus nerve stimulation may also be a choice
for patients who haven't responded to severe depression treatments, such as
antidepressant prescriptions.
Even though the revolution in pharmacology over the last few years has
captured much interest, recent advances in somatic interventions (physical,
non-pharmacological) are causing a recovery of interest in other methods.
For years, scientists have been interested in whether and how autonomic
functions modulate activity in the limbic system and sophisticated brain
cortex.
The vagus nerve is the longest nerve of the human body that roots from the
brainstem to the abdomen. The vagus nerve is a key component of the
autonomic nervous system . Modulation of gastro-intestinal motility and
secretion at the digestive tract level are linked tightly with the vagus nerve.
We can classify the vagus nerve based therapies as stimulation of the vagus
nerve, cutting of the vagus nerve (Vagatomy), and blocking of the vagus
nerve. Weight reduction frequently occurs in patients receiving vagus nerve
stimulation therapy. Therefore it is hypothesized that during dietary
intervention for weight loss, auricular electrics stimulation (AES), an
alternative of vagus nerve stimulation, accelerates weight loss by increasing
white adipose tissue browning and increases energy expenditure. All of
these methods have been applied by skilled clinicians, giving an option for
patients and healthy individuals to get better life endurance. Vagus nerve
based methods can be applied to laboratory animals to collect data. These
kinds of data warn scientists about side/adverse effects or give results of
first tried, non-approved methods.
Stimulation of vagus nerve therapy uses a pacemaker-like device
implementation. This kind of therapy has been used since 1997 to control
seizures in epilepsy patients. Additionally, patients with supraventricular
tachycardia , atrial fibrillation , and other cardiovascular illnesses have been
argued to perform vagal stimulation.
Numerous studies have identified extensive projections of the vagus nerve
via its sensory afferent connections in the nucleus tractus solitarius to many
brain areas. The sensory afferent cell bodies are located in nodose ganglia
and send information to the nucleus tractus solitarii (NTS). The nucleus
tractus solitarii projects the vagal sensory information to several regions of
the CNS, such as the locus coeruleus, the rostral ventrolateral medulla, the
amygdala, and the thalamus.
The term vagus nerve stimulation generally refers to techniques that are
used for stimulating the vagus nerve. Preclinical studies usually include
animals where the vagus was accessed through the abdomen and diaphragm
area. The present review provides a critical appraisal of the studies on vagus
nerve stimulation in animal models of seizures and epilepsy. So far, these
studies mostly applied short-term vagus nerve stimulation in seizure
models, demonstrating that vagus nerve stimulation can suppress and
prevent seizures and affect epileptogenesis. Implementation of vagus nerve
stimulation Therapy System is safe and feasible in dogs; however, seroma
formation, twisting of the lead, and dislodgement of the anchor tether were
common. However, vagus nerve stimulation refers to stimulus of the left
cervical vagus nerve. For this purpose, generally, a commercial device has
been used. The device for vagus nerve stimulation has been commercially
available for the treatment of resistant partial-onset seizures in epilepsy in
Europe since 1994 and in the United States since 1997. Typically, patients
with epilepsy are considering this method to control their seizures.
Commonly, these patients have already used more than 3 antiepileptic drugs
but could not escape epileptic attacks. Vagus nerve based methods are also
promising to decrease/terminate epileptic attack frequency. A 56 year-old
man with medically refractory partial epilepsy and anxiety, started having
partial seizures associated with staring, lips turning blue, and hands
wringing, at the age of nine. He started having several secondary
convulsions at age 16. After failing numerous anti-epileptic drugs (AEDs)
and ruling out epileptic surgery therapy, vagus nerve stimulation was
implanted at age 42. It had completely eliminated seizures and significantly
decreased the frequency of his partial seizures, with one per month.
Since its inception, clinicians, and especially surgeons are skeptical about
vagus nerve based therapies. The Food and Drug Administration (FDA )
has approved vagus nerve stimulation therapy for patients who are older
than 4 years. Also, these patients have focal (partial) epilepsy and suffer
from seizures that aren't well-controlled with medications. Furthermore,
scholars have been reviewing vagus nerve stimulation as a potential remedy
for a variety of conditions, including headaches, rheumatoid arthritis,
inflammatory bowel disease , bipolar disorder , obesity, depression and
Alzheimer's disease.
Cutting of the vagus nerve, also named vagotomy, is a now obsolete
therapy. This type of therapy was performed for peptic ulcer disease.
Vagotomy is currently being discussed as a less invasive alternative weight
loss procedure to gastric bypass surgery.
Proximal gastric vagotomy is a modification of truncal vagotomy, (truncal
vagotomy is among the 3 types of vagotomy. It is commonly used with
pyloroplasty or abdominal drainage to treat chronic peptic ulcer) which was
presented by Dragstedt for the treatment of duodenal ulcers in 1943. It is a
technically demanding surgery. Nevertheless, when executed by an
experienced surgeon, it is harmless and gives an optional remedy for ulcers
with minimal side effects1 .
Vagatomy is also discussed for cancer. The relationship of cancer and
vagatomy may seem weird. The accumulated evidence has indicated that
drug-induced hypochlorhydria can increase the risk of gastric cancer.
Preclinical studies reported hopeful results of vagotomy on chemically-
induced rodent models of gastric cancer. This was probably due to a
delayed gastric emptying, which later has been accounted for by including
an additional drainage procedure, e.g., pyloroplasty . In a recent study using
three different mouse models of gastric cancer (including genetically
engineered, chemically-induced, and Helicobacter pylori -infected mice),
either unilateral vagotomy or bilateral truncal vagotomy with pyloroplasty
was found to attenuate tumorigenesi in the denervated side of the stomach
at early preneoplastic stages, as well as at later stages of tumorigenesi2 .
The procedure curbs the feeling of hunger and is sometimes performed in
conjunction with putting bands on patients' stomachs, resulting in an
average weight loss of 43% at six months with diet and exercise.
Blocking of vagus nerve based therapy has been tried in weight loss studies.
A medical device produces high-frequency electrical algorithms to generate
intermittent vagal blocking. The aim is to evaluate the effects of vagal
blocking on excess weight loss. While this method is being applied, safety,
dietary intake, and vagal function should be controlled by clinicians
because unexpected effects of high-frequency electrical impulse may occur
in some individuals. Results suggest that intermittently blocking the nerve
with high frequency electrical impulses can help obese people lose weight
by reducing their appetite. In addition, there may be other unintended
consequences of disrupting signals to a particular portion of the vagus
nerve. Some experts worry that treatment aimed at treating the vagus nerve,
which reaches so many organs, may have unwanted side effects.
For most people, stimulation of the vagus nerve can be applied safely.
However, as with other surgical situations, it has particular risks with either
the surgery of the implant itself or the unexpected over stimulation of the
central nervous system. Surgical complications with implanted vagus nerve
stimulations are rare and are similar to the dangers of having other types of
surgery. The risks include: pain where the cut (incision) is made to implant
the device, infection, difficulty swallowing, and vocal cord paralysis, which
is usually temporary, but can be permanent. Also some of the side effects
and health problems associated with implanted vagus nerve stimulation can
include: voice change, throat pain, cough, hoarseness, headache, shortness
of breath, insomnia, worsening of sleep apnea, and tingling or prickling of
the skin. For most people, side effects are tolerable. They may lessen over
time, but some effects may remain bothersome for as long as you use
implanted vagus nerve stimulation.
The location and basic anatomy of vagus nerve
The Medieval Latin word “vagus” represents the word “wandering".
Vagrant, vagabond, and vague all share this same root. We can sometimes
confront the branches (majorly the superior laryngeal nerve and the
recurrent laryngeal) of the vagus nerve that are spoken of in plural and are
thus called vagi. Meanwhile, vagus is named the pneumogastric nerve due
to innervating both the lungs and the stomach.

Conventionally, the vagus nerve has been accepted as a parasympathetic

efferent nerve (controlling and regulating autonomic functions). However,
the vagus (cranial nerve X) is essentially a mixed nerve due to its function.
Approximately 80-85% of the vagus nerve has afferent sensory fibers.
Afferent sensory fibers carry information to the brain from the head, neck,
thorax, and abdomen. Efferent ones work the opposite way compared to
afferent nerves. Efferent motor fibers derive from the dorsal nucleus of the
vagus, whereas afferent motor fibers go to the nucleus ambiguous. Afferent
sensory fibers, which compose 80% of the left vagus, end in the nucleus of
the solitary tract. Midline raphe nuclei and locus cerulosis are likely the
path by which vagus nerve stimulation has anti-seizure and other
neuromodulator effects.
Both right and left vagus nerves derive from the brain in the carotid sheath,
lateral to the Carotid artery . The right vagus nerve gives rise to the right
recurrent laryngeal nerve, which hooks around the right subclavian artery
and arises into the neck between the trachea and esophagus . The right
vagus then crosses anteriorly to the right subclavian artery and runs
posterior to the superior vena cava and descends posterior to the right main
bronchus and contributes to cardiac, pulmonary, and esophageal plexuses. It
forms the posterior vagal trunk at the lower part of the esophagus and enters
the diaphragm through the esophageal hiatus.
Incoming sensory (afferent) connections of the vagus nerve provide direct
projections to many of the brain regions implicated in neuropsychiatric
disorders. Several neural networks play a role in the anatomy of afferent
connections of the vagus nerve. These connections reveal how vagus nerve
stimulation might be a gateway to the brainstem and connected regions.
These paths likely relate with the neuropsychiatric effects of the vagus
nerve, additionally inviting us to take theoretical considerations for
potential research and clinical applications of vagus nerve modulation.
Vagal efferent fibers originate in the dorsal motor nucleus of the vagus
nerve located in the medulla . In humans, these fibers innervate the
digestive tract from the esophagus to the splenic flexure from the rest of the
gut. However, some anatomists suppose that the vagus nerve innervates the
digestive tract in humans; whereas, in the rat, the vagus nerve innervates the
digestive tract except for the rectum. So we can say the role of the vagus
nerve can vary between species, because of its anatomical structure.
GABA and glutamate concentrations change with vagus nerve stimulation
in rats. This animal study has shown the consequence of vagus nerve
stimulation on neurotransmitters . As it is known, GABA is the inhibitory
neurotransmitter in the brain. Antiepileptic drugs increase the activity of
GABA to avoid seizures, whereas glutamate is an excitatory
neurotransmitter in our nervous system. Glutamergic drugs, also known as
glutamate regulators, are being used for neuropsychiatric diseases.
Glutamate is not the only neurotransmitters that are affected by the vagus
nerve. There is also another biochemical molecule that can be affected by
the vagus nerve.
It is logical to carefully evaluate potential cardiac and gastrointestinal
effects of vagus nerve stimulation. In other words, first, we should avoid
any side/adverse effects on the cardiovascular system. In this content, some
data was collected on more than 250 epilepsy patients in clinical trials while
receiving vagus nerve stimulation. Holter, monitoring results from clinical
studies in epilepsy, indicated no significant changes from baseline in
cardiac function during stimulation 3 , 4 .
The roles in weight loss
Excessive body weight has been a public health problem all over the world,
particularly in wealthy countries. Governments and health authorities have
focused on this issue to canalize their citizens to being fit because there is
plenty of evidence that asserts excessive body weight can cause diabetes,
cardiovascular disorders, hypertension , and hyperlipidemia . To avoid these
diseases and other unwanted disorders, health professionals and dietary
experts spend more effort by providing individuals with a base of
information that makes them more knowledgeable of food choices. Also
nutrition education programs provide information on the role of nutrition in
health promotion and disease prevention, sports nutrition, and nutrition for
pregnant and lactating women. Taking into account that dieticians’
schedules sometimes can be challenging for some people while they are
maintaining it for a long time, vagus nerve based therapy may be an option.
Why do some people feel full after eating a small amount of food and other
people are still hungry until they eat a big portion? The answer might be in
the understanding of the vagus nerve’s working principle. The vagus nerve
connects our gut to our brain, and as we discussed, it’s an important part of
the parasympathetic nervous system (the “rest and digest” response). The
physical bulk of food in the stomach conducts satiety signals up the vagus
nerve to our brain. This is how our brain knows to stop feeling hungry after
a meal. Nutrient sensing and neurotransmitters produced in the gut, like
serotonin and ghrelin, can also send hunger and fullness signals up the
vagus nerve to the brain. Collectively, we can assert that the vagus nerve
modulates the sense of food intake pattern and satiety .
A group of scientists from Canada executed a clinical study to unearth
whether the vagus nerve affects obese individuals. They performed a human
study in 3 different centers (Norway, Mexico, and Canada). This study was
conducted in obese individuals whose body mass index was 35–50 kg/m2 .
Electrodes were implanted laparoscopically on the vagus nerve near the
esophagogastric junction to provide an electrical block. Patients were
followed for 6 months for body weight, measuring the values of
electrocardiogram, dietary intake, satiation, satiety, and plasma pancreatic
polypeptide. Patients were free to continue their normal habitual eating.
Because this study aimed to assess device effects alone, no diet or exercise
were included. The result of this study is hopeful. Intra-abdominal vagal
blocking was found significantly to decrease excessive body weight.
Additionally, application of this method was confirmed by doctors as
clinically safe 5

Food interacts
with sensors all along the digestion canal to provide the brain with
information regarding its ingredients, energy content, and beneficial or
toxic effect. The vagal afferent pathway innervates the gastrointestinal area.
The pancreas and liver provide a rapid and discrete account of digestible
food in the digestion canal, as well as circulating energy metabolism. The
vagal efferent pathway also plays a role in digestion in the sympathetic
nervous system and hormonal mechanisms. So we can say the rate of
nutrient absorption, packing, and mobilization are related with the vagus
nerve, either the afferent or efferent pathway.
Even though vagal sensory mechanisms play a critical role in the
mechanism of satiation, there is insufficient proof suggesting an important
role in long-term energy homeostasis. However, increasing recognition of
vagal involvement in the putative mechanisms , making surgeries the most
effective treatment for obesity, should greatly stimulate future research to
discover more information regarding the detailed transduction mechanisms
in the periphery and the neuronal signaling pathways circulating vagal
information across the neural ways 6 . Vagal afferent neurons play an
important role in the control of food intake by signaling nutrient type and
quantity to the brain. Recent findings are broadening our view of how vagal
afferent neurons impact not only food intake but also energy homeostasis.
Key Points in one page
Stimulation of vagus nerve therapy is administered by a
pacemaker-like device. This kind of therapy has been used
since 1997 to ameliorate seizures in patients who have
treatment-resistant epilepsy; in addition, patients with
supraventricular tachycardia , atrial fibrillation , and other
cardiovascular illnesses have been argued to perform vagal
stimulation.

Vagal efferent fibres originate from the dorsal motor nucleus,

which is located in the medulla . These fibres innervate the
digestive tract from the esophagus to the splenic flexure and
the rest of the gut.

Why do some people feel full after eating a small amount of

food and other people are still hungry until they eat a big
portion? The answer might be in the understanding of the
vagus nerve working principle.
A group of scientists executed a clinical study to unearth
whether the vagus nerve affects obese individuals; intra-
abdominal vagal nerve blocking significantly decreased
excessive body weight.
 SECTION 4: THE
GASTROINTESTINAL
SYSTEM AND
PARTICULAR
INFLAMMATORY EVENT
S
Vagus nerve function in gastrointestinal system
The gastrointestinal system, also defined as the digestive system, is
exclusively constructed to perform its dedicated function of turning food
into energy. The basic functioning of our gastrointestinal system is closely
related to our optimal nervous system. The many parts of the digestive
system work together and communicate with each other for maintaining the
best digestion. Mechanical and chemical activities of the gastrointestinal
system start at the mouth and then continue through the pharynx,
esophagus, stomach and intestines to the rectum and anus 1 .
The journey of foods and drinks through our body is long as it encounters
physical and chemical digestive elements. The process of digestion contains
six actions: ingestion, propulsion, mechanical/physical digestion, chemical
digestion, absorption, and defecation. All these digestive processes are
associated/regulated with different nerves and hormones. There are
numerous accessory organs that assist the tract by secreting enzymes to help
digest food into its component nutrients. Thus the salivary glands, liver,
pancreas and gallbladder all have important functions in the digestive
system. Food is propelled along the length of the gastrointestinal tract by
peristaltic movements of the muscular walls2 . These movements are
controlled by parasympathetic nerves as well as the vagus nerve.
The left and right vagus is in line with the esophagus through the
diaphragmatic hiatus. Upon entering the abdominal cavity, the left and right
vagus become the anterior and posterior vagus, respectively. It should be
kept in mind that each trunk receives fibers from both cervical vagus
nerves. The quantity of posterior and anterior trunks passing through the
diaphragmatic opening is variable, up to two in the former and three in the
latter. The anterior trunk dispenses gastric branches to the anterior of the
stomach and turns off into the hepatic branch. Besides innervating the liver,
the hepatic stem branches off to the pylorus and the proximal part of the
duodenum and pancreas. The large intestine receives additional
parasympathetic innervation through the pelvic splanchnic nerve (S2-S4),
which ends in the pelvic plexus and becomes the colonic and rectal nerve3 .
The afferent vagus nerve innervates the gastrointestinal tract via vagal
terminals both in the lamina propria and in the muscularis externa.
Likewise, the efferent vagus nerve fibers only interact with neurons of the
enteric nervous system. The enteric nerve contains the submucosal plexus
and external muscular compartment of the myenteric plexus. By means of
electrophysiological studies, it was demonstrated that preganglionic
parasympathetic fibers (both vagal and sacral innervation) directly interact
with multiple postganglionic myenteric neurons by forming varicosities,
whereas few vagal fibers communicate with submucosal neurons4 .
The preganglionic innervation of the gastrointestinal tract shows typical
rostro-caudal gradient with the peak density of innervated myenteric
neurons in the stomach and duodenum followed by an advanced reduction
in the small intestine and colon. It is also taken into account that gastric
myenteric neurons are activated by vagal input5 .
Vagal fibers are arranged throughout the gastrointestinal system tract and
interact with the gut to regulate food intake, ingestion rate, the digestion
canal barrier, and immune response for alerted/normal conditions. It is
known that nutrition intake leads to satiety through the stimulation of
several pathways, releasing various peptides from endocrine cells to the
digestion canal.
In addition to chemosensory signal transduction, the afferent fibers of the
vagus are also activated by gastric swollenness through the stimulus of
afferent vagal mechanoreceptor in the gastrointestinal tract. Two candidate
mechanoreceptors of the vagus nerve have been defined as the
intraganglionic laminar ending and intramuscular arrays.
Translation between gut and brain
Brain and gut communication is one of the most interesting and
complicated arches. Either the brain sends command signals to our
gastrointestinal system or the gastrointestinal system sends
feedback/commands to the brain. Regulation of this bidirectional signal
mechanism is maintained via nerves, hormones, and other related
substances. Hundreds of millions of neurons make a connection between
the brain and the enteric nervous system, the part of the nervous system that
is tasked with controlling the gastrointestinal system. This network
monitors the entire digestive tract from the esophagus to the anus. The
enteric nervous system is so extensive that it can modulate as an
independent entity without input from our central nervous system, although
they are in consistent communication.
Nearly all operations of the enteric nervous system are supervised by the
brain and central nervous system. The central nervous system keeps in
touch with the gut via the sympathetic and parasympathetic nerves of the
autonomic nervous system .
The bidirectional communication of the brain and gastrointestinal system is
maintained via neurons, hormones, and chemical neurotransmitters . These
providers are not only sending messages to the brain about the status of our
gut but also playing a role in regulating the gut environment. The rate at
which food is being moved, and how much mucus is lining the gut, has a
direct effect on the environmental conditions the microbiota experiences.
The gut microbiota can affect the body’s level of the potent
neurotransmitter serotonin , also known as the happiness hormone. Some of
the most prescribed drugs all over the world for treating anxiety and
depression, like sertraline, paroxetine, and citalopram work to modulate
levels of serotonin. Meanwhile, serotonin is one of numerous biochemical
messengers that the microbiota impacts, influencing our mood and
behavior.
It is estimated that the human enteric nervous system contains about 200–
450 million neurons. That is the largest amount of nerve cells in the human
body that take place in the gastrointestinal system. Meanwhile, the enteric
nervous system is like the brain of structure, function, and chemical coding.
The enteric nervous system controls the movement of water and electrolytes
between the gut lumen and tissue fluid compartments. Enteric neurons are
coded by a combination of markers that give each neuron type a unique
signature. Correlation of chemical coding with pharmacological analysis of
transmission indicates that individual enteric neurons all use two or more
transmitters. The enteric nervous system contains full reflex circuits for
control of intestinal motility, fluid transport, blood flow and nutrient
handling. So, some scientists have described the GIS as “the

second
brain” .
6

The enteric nervous system ascends from the neural crest cells of the vagal
origin and consists of a nerve plexus rooted in the intestinal wall, extending
across the whole gastrointestinal tract from the esophagus to the anus.
Gastrointestinal blood flow, epithelial cell functions, and secretion are
regulated by the submucosal plexus. The myenteric plexus mainly regulates
the relaxation and contraction of the intestinal wall7 .
The intestinal barrier regulates major enteric events, such as immune
response, identifying nutrients, motility, micro vascular circulation, and
epithelial secretion of fluids, ions, and bioactive peptides .
Communication and translation between the vagal nerve and the enteric
nervous system is closely associated with cholinergic activation through
nicotinic receptors. Interaction of the enteric nervous system and the vagal
nerve as a part of the central nervous system leads to a bidirectional
movement of information. In contrast, the enteric nervous system in the
small and large bowel is able to perform its work via vagal control.
Regulation of muscle activity and motility, fluid fluxes, mucosal blood
flow, and also mucosal barrier function are activated with presence of
acetylcholine8 .
Aging and cell loss in the enteric nervous system are associated with
complaints, such as constipation, defecation problem, and incontinence. We
can confront some individuals whose enteric nervous system is deactivated
or disrupted. To avoid these kinds of problems, we should keep in mind that
vagus nerve activity has a fundamental role in our gastrointestinal system.
Vagus Nerve as Modulator of Intestinal Immune
regulation
For many decades, it has been acknowledged that a complex interplay
exists between the nervous system and immune cells. Our central nervous
system receives a sensory impulse when the presence of inflammation
occurs in any organ of the system. Therefore, the response for the
inflammatory mechanism is initiated with two specific pathways:
neuroendocrine and neural routes.
Activation, inhibition, and control of the native immune system is vital for
maintenance of homeostasis in the human body. The central and peripheral
nervous systems play a critical role in immunoregulation. The central
nervous system actively responds to acute immune challenges by altering
body temperature up and down, regulating specific sympathetic pathways.
These pathways are primarily involved in attenuating organism’s responses
initiated by an immune challenge.
Bowel structure is so complicated that specialized epithelial cells constitute
barrier surfaces that separate mammalian hosts from the peripheral
environment. The gastrointestinal tract has a barrier that is specially adapted
to colonization by commensal bacteria (living in a relationship that benefits
from another organism without hurting or helping it) that aid in digestion
and markedly influence the development and function of the mucosal
immune system 9 .
Microbial colonization also has a risk of infection and inflammation when
epithelial or immune cell homeostasis is disrupted. The gastrointestinal tract
is the largest reservoir of commensal bacteria in the human body, providing
nutrients and space for the survival of microbes while concurrent mucosal
barriers confine the microbial population. The gastrointestinal epithelium,
linked by tight junction, not only physically separates the microbiota from
the lamina propria, but also secretes the proinflammatory cytokines and
reactive oxygen species; this occurs in response to pathogen invasion and
metabolic stress and serves as a sentinel to the underlying immune cells.
The gastrointestinal epithelium undertakes commensal and pathogenic
microorganisms via physical and biochemical barriers. Furthermore,
intestinal epithelial cells can detect and answer to microbial stimuli to
reinforce their barrier function.
Together, these observations strongly indicate the brain is able to modulate
the splenic immune response indirectly or directly via circulating cytokines
and via afferent input from sensory fibers. The splenic immune reaction has
an important role during systemic inflammation, since splenic macrophages
are the major source of TNF-α in sepsis. Collectively, we can say immune
regulation on the gastrointestinal system and the whole human body is
strongly associated with the parasympathetic system as well as vagus nerve
activities10 .
Vagus nerve stimulation strongly inhibits splenic TNF-α production in a
model of systemic inflammation, introducing the concept of the cholinergic
anti-inflammatory pathway. This anti-inflammatory reaction is mediated by
the reduced activation of splenic macrophages expressed in the alpha7
nicotinic receptor (α7nAChR). Also it should be remembered that the
release of acetylcholine arranged by memory T cells, namely, interacts with
α7nAChR and inhibits the secretion of pro-inflammatory cytokines via the
JAK-STAT pathway. The JAK-STAT signaling pathway is a chain of
relations between proteins in the cell and plays a role in processes such as
immunity, cell division, apoptosis and tumorogenesis. The chlolinergic
nervous system attenuates the production of pro-inflammatory cytokines
and inhibits the inflammatory process. It is originally indicated that the key
mediator of the chlolinergic anti-inflammatory pathway acetylcholine,
inhibits cytokine release directly via the α7 nicotinic Ach (nAChR) receptor
expressed on machrophages. However, more recent findings also point
towards the vagus nerve as an indirect modulator of innate inflammatory
processes, exerting it’s anti-inflammatory effects via postganglionic
modulation of immune cells in primary immune organs .
Many scientific studies have reported the beneficial effect of vagus nerve
stimulation in inflammatory models such as hemorrhagic shock,
pancreatitis, and collagen-induced arthritis11 .
The cholinergic anti-inflammatory pathway in the gastrointestinal tract is
closely linked with the vagus nerve because it is largely innervated by the
vagus nerve. Electrical, nutritional and pharmacological activation of the
vagal pathway prevents surgical induced inflammation. Cholinergic anti-
inflammatory pathway activation also has an effect on intestinal
inflammation in diabetic-induced gastro paresis, colitis, and septic ileus.
Likewise, severe colitis is also correlated with the decline of mucosal levels
of acetylcholine in depression. As we discussed with the spleen, the anti-
inflammatory response of the cholinergic anti-inflammatory pathway is
mediated through α7nAChR macrophages12 .
Deficiency of α7nAChR significantly revoked the vagal anti-inflammatory
effect. It can be understood that the beneficial effect of vagus nerve
stimulation depends on α7nAChR expression on immune cells. As in the
spleen, the cholinergic anti-inflammatory pathway is not intermediated by
direct interaction between α7nAChR macrophages and efferent vagal fibers
but rather via the modulation of cholinergic enteric neurons in proximity of
intestinal α7nAChR expressing macrophages.
To summarize, electrical stimulation of the vagus nerve has been used as an
option for therapeutic devices for treatment-resistant epilepsy and
depression. Currently, the anti-inflammatory effects of vagus nerve
stimulation have been under development for clinical trials in patients with
rheumatoid arthritis, Crohn’s disease, and postoperative ileus. Future
aspects from clinical trials and basic research may be an innovative and
powerful new therapeutic instrument for the cholinergic anti-inflammatory
pathway13 .
Modulation of inflammatory process
The term inflammation can be defined as our body's way of protecting itself
from infection, illness, or injury. Although excessive inflammation can
force our body and make us sick, we should keep in mind that the
inflammatory response is one of the vital processes in our body. Production
of white blood cells, immune cells, and substances called cytokines are the
soldiers of the human body that combat infection and other foreign things.
Inflammation is caused by numerous physical reactions triggered by the
immune system in response to a physical injury or an infection. So, it is
important to know that inflammation is part of the healing process. We can
conclude that reducing inflammation is sometimes helpful, but it is not
always necessary for a healthy body.
Typical signs of acute inflammation are redness, pain, heat, and swelling.
Acute inflammation usually occurs when we are confronted with influenza,
cold, and detrimental substances. On the other hand, chronic inflammation
can occur without any visible symptoms. While they are unnoticeable/light
symptoms, this type of inflammation can cause more serious illnesses, such
as diabetes, cardiovascular disorders, fatty liver disease, hypertension, and
cancer. The most common markers of inflammation include C-reactive
protein (CRP), homocysteine, TNF α, and IL-614 .
The inflammation process also makes it easier for immune system cells to
pass through small blood vessels; therefore, these cells can accumulate
easily in the affected tissue. Mucous membranes also release more fluid
when they are inflamed. For example, this happens when you have a stuffy
nose and the membranes coating your nose are inflamed. Then the extra
fluid can help to flush the viruses out of your body.
Inflammation doesn’t always help our healthy body. We can see in some
diseases that the immune system fights against the body’s own cells. The
result of this fight can be chronic diseases. Rheumatoid arthritis, psoriasis
(chronic skin disease), inflammatory bowel diseases, Crohn’s disease, and
ulcerative colitis are the most common ones that are closely related with
untreated chronic inflammation. Collectively known as chronic
inflammatory diseases, these diseases can continue with us for years or
even a lifetime15 .
In conclusion, physiological inflammation is almost necessary for our
body’s immune response. Keep in mind that excessive and chronic
inflammation can cause some diseases.
The vagus nerve inhibits inflammation
Numerous studies have shown that people with higher vagus nerve activity
have lower levels of cortisol , the stress hormone, and lower levels of TNF-
α, which is an inflammatory immune marker. However, recent studies have
not only confirmed the connection between the nervous and immune
systems. Scientists have elucidated that the cytokine-inhibiting mechanism,
termed the inflammatory response, can be dependent upon vagus nerve
signals.
The afferent arc of the vagus nerve is activated by cytokines and is
projecting to neurons of the medullary nucleus ambiguous. Meanwhile, the
efferent vagal arc directly suppresses the cytokine production and, in that
way, inhibits inflammation and prevents probable damage of excessive
inflammation. Experimental data obtained in rats proposed that, via vagal
stimulation, cytokine production can be inhibited and arthritis is decreased
as a result of this inhibition16 .
Although the mechanism (electrical stimulation of cervical vagus nerve) is
unknown and requires significant investigation, results from both animal
and initial clinical investigations suggest a potential benefit of efferent
cervical vagus nerve stimulation in relieving systemic and local
inflammation. Most studies for cervical vagus nerve stimulation
investigations stimulate the cervical vagus nerve, leading to activation of
both afferent and efferent pathways. While these approaches are sufficient
for elucidating acute effects in animal investigations, clinical translation of
selective afferent or efferent cervical vagus nerve stimulation requires a
safer and more effective alternative method.
Various studies have examined stimulation via custom electrode geometries
and different stimulation waveforms. These approaches suffer from clinical
challenges, such as patient-to-patient variations in nerve anatomy as well as
surgical placement and movement of electrodes. Besides, a cervical
vagotomy is not desirable in clinical settings due to the fact that a
significant amount of parasympathetic control is exerted on the viscero-
motor systems through the vagus nerve. A safe, effective, and reversible
selective afferent cervical vagus nerve stimulation or efferent cervical vagus
nerve stimulation method requires more development before using to
control excessive/chronic inflammation in humans17 .
Concerning vagus nerve stimulation to reduce the frequency of epileptic
seizures, Koopman et al. presented that the vagus nerve stimulation has an
effect also on the activity of rheumatoid arthritis. The vagus nerve
stimulation significantly inhibited TNF-α production. Taken together, these
results assert that vagus nerve stimulation modulates TNF-α production and
reduces inflammation in humans18 .
Studies also show the vagus nerve regulates inflammation throughout the
body, including inflammation associated with obesity. In section 2, as we
discussed the roles of the vagus nerve on weight loss; inflammation could
also be a key modifier of obesity.
Key Points in one page
Vagal fibers are located throughout the gastrointestinal system
tract and interact with the gut to regulate food intake patterns,
ingestion rate, digestion canal barrier, and immune response
for alerted/normal conditions.

Activation, inhibition, and control of the native immune

system are indirectly modulated by the vagus nerve. The
cholinergic anti-inflammatory pathway in the gastrointestinal
tract is tightly linked with the vagus nerve.
Several scientific studies have reported that people with higher
vagus nerve activity have lower levels of cortisol and lower
levels of TNF-α, which is an inflammatory immune marker.
 SECTION 5: REGULATION
OF THE
GASTROINTESTINAL
SYSTEM
Vagus nerve and gastrointestinal system arch
The vagus nerve transmits an extensive range of signals from the digestive
system and other organs to the brain. The connection between the brain and
the enteric nervous system, also known as the brain–gut axis, enables the
bidirectional association between the brain and the gastrointestinal tract.
This axis is responsible for maintaining physiological homeostasis and
connecting the emotional and cognitive areas of the brain with peripheral
intestinal functions. Emotional situation, immune activation, intestinal
movements and permeability, enteric reflex, and particular endocrinal
signaling pathways are some procedures under effect of brain-gut axis
regulation. This brain–gut axis comprises the brain, spinal cord, autonomic
nervous system , and hypothalamic–pituitary–adrenal (HPA) axis.
The view that the commensal intestinal microbiota can affect brain function
has at least one clear clinical origin: the observation that orally administered
antibiotics can heal encephalopathy in patients with liver disease. Moreover,
psychiatric disorders frequently coexist with common gastrointestinal
conditions, such as irritable bowel syndrome, which are also associated
with disturbances of the intestinal microbiota1,2 .
Animal based research has also extended the idea of microbiota–brain
interactions to other psychiatric disorders, as well as to immunologically
mediated neurological conditions, such as multiple sclerosis. Therefore, this
emerging field has the potential not only to increase our understanding of a
broad spectrum of human disease, but also to generate novel therapies for
these conditions based on the identification of mechanisms underlying
microorganism–human gastrointestinal system interactions3 .
The enteric nervous system integrates physiological gut motility and
secretion, as well as modulates immune activity. The afferent limb
comprises sensory nerves that contribute to gut reflexes and carry messages
to the brain. This information includes signals about harmful stimuli, such
as gut distension, as well as potentially dangerous signals, including the
existence of microbial endotoxins or pro-inflammatory cytokines.
The autonomic nervous system connects the gut and the brain via
sympathetic and parasympathetic nerves. The vagus nerve is a main carrier
for signals that originate from the foregut and the proximal colon, whereas
sacral parasympathetic nerves innervate the distal colon. However, the
sympathetic system primarily has an inhibitory influence on the gut,
decreasing intestinal motor function and secretion via the release of
neurotransmitters for instance noradrenaline.
Communication between the limbic and autonomic systems provides the
neural circuit board underlying the strong link between behavior and gut
function in health and disease. The humoral components of the gut–brain
axis consists of the hypothalamic–pituitary–adrenal axis, the
enteroendocrine system, and the mucosal immune system. Enteroendocrine
cells produce molecules such as cholecystokinin and ghrelin. Both
hormones regulate appetite and 5-hydroxytryptamine, which has a wide-
range of effects on gut and brain functions.
Indirectly, short-chain fatty acids have an effect on vagal afferent terminals,
whereas the long-chain fatty acids activate vagal afferents via a
cholecystokinin dependent pathway. Cholecystokinin is also present in
enteric vagal afferent neurons, in the cerebral cortex, in the thalamus, basal
ganglia, hypothalamus, and dorsal hindbrain, in addition to its functioning
as a neurotransmitter. Furthermore, cholecystokinin directly activates vagal
afferent terminals in the nucleus tractussolitari by increasing calcium
release.
Scientific evidence supports that cholecystokinin can activate neurons in the
hindbrain and intestinal myenteric plexus (a plexus that provides motor
innervation to both layers of the muscular layer of the gut) in rats and that
vagotomy or capsaicin treatment results in an attenuation of cholecystokinin
induced proto-oncogene (Fos ) expression in the brain. There is also
considerable evidence that high levels of cholecystokinin can induce
feelings of anxiety. Consequently, cholecystokinin is used as a challenge
agent to model anxiety disorders in humans and animals. In conclusion,
adding this information to the role of the vagus nerve (as discussed in
section 3) can give us more insight about how healthy gastrointestinal
maintenance is strongly related with a strong mind/mood as well as a
healthy physiological life.4-6 .
The role of microbiota and balancing of the gut
microbiome
Humans cohabitate in a mutualistic relationship with the intestinal
microbiota, a complicated microbial ecosystem that exists largely in the
distal bowel. The lower gastrointestinal tract contains approximately 100
trillion microorganisms, most of which are bacteria. More than 1,000
bacterial species have been identified in this microbiota; the majority of
these bacteria are strict anaerobes .
Bacteria, fungi, and viruses live together in a harmonic and dynamic
equilibrium in the gastrointestinal system. This microbial community starts
to colonize in the body before we are born and survives in the
gastrointestinal system in a mutualistic relationship until death. The
intestinal microbial community plays a role in contributing to nutrient
metabolism, adjusting metabolic functions, modulating the immune system,
and defending us from toxic/detrimental pathogens7,8 .
It should be remembered that the microbial community plays a vital role in
the human body as nearly all vital organs are near the brain. We can survive
without some organs, including the spleen, gallbladder, tonsils and
appendix, but we wouldn’t be alive for long without microbiota in the
gastrointestinal system. So plenty of strategies have emerged to maintain
this mutual ecosystem in our body. Some of them can be listed as;

Increasing intake of fiber foods; fiber intake has been

presented to reduce heart disease and some cancers, as well as
decrease weight gain.
Eating a diverse range of diets; Consuming different kinds of
foods and drinks help either our body or different microbial
species.
Eating fermented foods; the fermentation process helps
bacteria or yeasts convert the sugars in food to organic acids
or alcohol. Yogurt, kimchi, sauerkraut, kefir, kombucha, and
 tempeh are some of the most prominent fermented nutrients
that support the gut ecosystem.
Avoiding too many artificial sweeteners; non-natural
sweeteners are widely used for replacing sugar. Nevertheless,
some studies have reported that these sweeteners can
negatively affect the gut microbiota.
Eating prebiotic foods; prebiotics are foods that evoke the
growth of cooperative microbes in the gut. Some of the
examples of the prebiotic foods include dandelion greens,
chicory root, garlic, onions, leeks, asparagus, barley, konjac
root, cocoa etc. They are chiefly fiber or complex carbs that
can't be digested by human cells. Instead, certain species of
bacteria break them down and use them for fuel.
Plant-based diet; several studies have reported that vegetarian
diets may benefit the gut microbiota. The reason may be due
to their higher fiber contents.
Foods that contain rich polyphenols; polyphenols are the plant
compounds that have numerous health benefits, including
reductions in blood pressure, inflammation, cholesterol levels,
and oxidative stress as well as gut microbiota. Some of the
foods with phenols include: berries, beans, soy, vegetables,
nuts, non-berry fruits etc.
Probiotic supplement; probiotics are the microorganisms that
are usually bacteria that exert a specific health benefit when
consumed. Although probiotics cannot generally colonize the
intestines, they may benefit health by varying the overall
composition of the microbiota.
Balancing of microbiota in the guts and other regions of our body is so
crucial that many strategies have been developed. Researchers have focused
on this issue via different approaches, in addition to nutritious pathways.
More recent therapeutic approaches have been proposed as phage therapy,
fecal transplantation, and bacterial consortium transplantation, and a still
investigated approach based on predatory bacteria. All of these strategies
focus on the same goal of switching harmful microbes with more favorable
ones to restore the microbial ecosystem9 .
Several disorders, such as inflammatory bowel disease, celiac disease,
obesity, and metabolic disorder, are related with disruptions in maintenance
of optimum gut community10 . Nobel laureate Eli Metchnikoff (1845–1916)
said that most diseases begin in the digestive tract when good bacteria are
no longer able to control bad bacteria.
Prebiotics and probiotics’ role in gastrointestinal
system
Probiotics and prebiotics play a major role in nutrition related
gastrointestinal system health. Even though they sound similar, the two play
diverse roles for human body health. Summarily, we can define probiotics
as beneficial bacteria, while prebiotics are food for these bacteria .
The original definition of prebiotics was first presented by Gibson and
Roberfroid in 1995; “Non-digestible dietary ingredients that beneficially
affect the host by selectively stimulating the growth and activity of bacteria
in the colon, thus help to improve host health.” This definition includes the
elements that can be natural and produced chemically. Many dietary fiber
substances are included under this definition.
The gut bacteria is referred to as the gut flora or gut microbiota, which
execute many vital functions in the body. Ingesting balanced amounts of
both pro- and prebiotics can help to ensure that we have the right balance of
these bacteria. The good bacteria in the digestive tract can combat harmful
bacteria and fungi. They also send messages to the immune system as well
as regulate the inflammation process in the body. Additionally, some of the
gut bacteria are responsible for the synthesis of vitamin K and short-chain
fatty acids. Short-chain fatty acids are an important nutrient source of the
cells lining the colon.
Pre and probiotics have also helped local intestinal cells to preserve the
barrier of gastrointestinal tract. Promoting a strong gut barrier is maintained
for keeping out harmful substances, viruses and bacteria. There is recent
scientific evidence to support that this process also reduces inflammation
and may reduce the risk of particular cancer cells .
 Certain probiotics
have been found effective in relieving constipation. Due to probiotics being
taken by mouth, their efficacy depends on how well they can live against
the acidic environment of the stomach and gastrointestinal tract. The
highest quality probiotics will pass through the stomach still intact and
move into the intestines where nutrients are absorbed. Probiotics do most of
their healing and work in the intestines.
A healthy digestive system contracts and relaxes in a physiological normal
frequency. The other benefits of probiotics in the bowel is adjusting
movements of the intestinal tract. By aiding in protein absorption,
probiotics can also help the body to recover after workout and reduce
muscle strain11,12 .
Stomach and the vagus nerve
In the human stomach, neural and hormonal signals are produced to
transmit messages for satiety and starvation to the brain via the afferent
vagal nerve and blood circulation. Numbers of peptides are playing a role in
the regulation of food intake via the gut-brain communication axis by
neuroenteric peptides . The afferent fibers of the vagus nerve are the major
neuronal linkage between the gastrointestinal tract and the nucleus of the
solitary tract in the brain. Various metabolites in the intestinal tract can
cause it to transmit satiety signals to the nucleus of the solitary tract via the
vagal afferent neurons .

Ghrelin, also
known as the satiety hormone, is responsible for the secretion of growth
hormone, food intake, and body weight gain. As it is known, the
hypothalamus plays a major role in the regulation of feeding. Ghrelin
activates the process of protein production and neuropeptide Y, producing
neurons localized in the hypothalamus. Secretion of ghrelin is up-regulated
under conditions of negative energy balance, such as starvation, insulin-
induced hypoglycemia, cachexia, and anorexia nervosa, whereas it is down-
regulated under conditions of positive energy balance, such as feeding,
hyperglycemia, and obesity.
Ghrelin is thought to be able to enter the brain across the blood brain
barrier. Although ghrelin’s orexigenic activity (increased appetite) balance
may depend on the vagus nerve, it has not been clarified how ghrelin sends
information from the stomach to the brain. Taking into account that visceral
sensory information is transmitted to the brain through the afferent vagus
nerve can help us to understand vagus nerve and stomach relationship via
ghrelin hormone activity13 .
There is a close relationship between ghrelin producing cells and vagal
afferent terminals in the stomach. Vagal afferent neurons have been known
to produce numerous bioactive peptides, including substance P and
calcitonin gene–related peptide relative to feeding. Vagal afferent fibers
have a continuous low-frequency spontaneous discharge that is modulated
by sensory inputs. The existing electrophysiological studies supposed that
the effective dose of ghrelin to stimulate feeding and

growth
hormone secretion suppressed gastric vagal afferent discharge.
Japan scientists researched the role of the gastric afferent vagal nerve in
ghrelin-induced feeding in animals. They showed that ghrelin hormone
predominantly stimulated feeding patterns and secretion of growth hormone
GH by gastric vagal afferents. Selective chemical and surgical vagotomy
methods were applied to the animal’s stomach. The results were reported
that blocking of the gastric vagal afferent nerves decreased ghrelin-induced
feeding, growth hormone secretion. In addition, they asserted that ghrelin
receptors are synthesized in vagal afferent neurons and transported to the
afferent terminals. This study indicated that the gastric vagal afferent is one
fundamental pathway to transfer ghrelin’s signals for starvation and growth
hormone secretion. Consequently, perivagal capsaicin application and
vagotomy affected some vital neuropeptides and hormones that can give
inspiration for advanced human studies14 .
In addition to satiety sensation, the stomach sends ghrelin-derived hunger
signals to the brain via vagal afferents. Ghrelin also provides a new insight
into the vagus-mediated growth hormone secretion, which interacts with
vital body functions. Ghrelin and growth hormone are also enrolled as
anabolic signaling molecules during energy depletion. We can conclude that
ghrelin production in the stomach seems logical considering these anabolic
effects. The future advanced studies on the vagus nerve’s role in ghrelin
modulation would extend our understanding of how energy balance and
growth are controlled by the stomach.
Key Points in one page
Bidirectional interaction between the brain and the
gastrointestinal tract is mostly under control of the vagus
nerve. The vagus nerve is a main carrier for signals that
originate from the foregut and the proximal colon.

Nobel laureate Eli Metchnikoff asserted that most diseases

begin in the digestive tract when good bacteria are no longer
able to control bad bacteria. The microbial community in our
gastrointestinal system has vital roles; we cannot survive
without them.

Pre and probiotics help local intestinal cells to maintain an

optimum barrier of the gastrointestinal tract.
Visceral sensory information is transmitted to the brain
through the afferent vagus nerve. The relationship between the
vagus nerve and stomach is also under control of the ghrelin
hormone.
 SECTION 6: THE EFFECTS
ON NEUROPSYCHIATRIC
DISORDERS
Vagus nerve stimulation for depression
The FDA has correspondingly approved vagus nerve stimulation for the
treatment of depression in adults who have chronic and treatment-resistant
depression. However, the FDA declared that patients should continue
standard depression treatments along with vagus nerve stimulation.
Vagus nerve stimulation alters concentrations of neurotransmitters or their
secondary products. As it is known, neurotransmitter balance or activity can
be disrupted in central nervous system regions in mood disorders. In
addition to vagus nerve effects on neurotransmitter balance, other
mechanisms such as neuroinflammation can play a role in modulation of
neuropsychiatric disorders.
Scientists from the University of Texas Southwestern Medical Center have
reported that stimulation of the vagus nerve was well tolerated by
participants who have nonpsychotic major depressive disorder (210
patients) and nonpsychotic bipolar disorder (25 patients). Only 3
participants left the study because of adverse effects; 232 patients
completed this human study. However, the results were discussed by
scientists as: did not yield definitive evidence of short-term efficacy for
stimulation of vagus nerve in treatment-resistant depression.1
Stimulation of the vagus nerve is undergoing investigation as a treatment
for patients with resistant major depressive episodes. The basis of this
indication is the same as the utility of anticonvulsant medications, such as
mood stabilizers and antidepressants in mood disorders. The evidence from
animal and human research suggests that vagus nerve stimulation has
altered the concentrations of neurotransmitters, which are tightly related
with mood disorders. Some of these neurotransmitters are serotonin,
norepinephrine, gamma aminobutyric acid, and glutamate 2 .
The other name of serotonin is the happiness hormone. This hormone has
numerous effects on our body, such as regulation of awake-sleep duration
and circadian rhythm. Besides, human mood condition is affected by
abnormal circadian rhythm and an abnormal circadian rhythm can worsen
our mood. So even only unbalanced serotonin regulation is a causative
factor for depression. Scientists therefore discovered serotonin reuptake
inhibitors for healing neuropsychiatric disorders to get the level of serotonin
in an optimum range. When we take into account that even one
neurotransmitter has a potential for maintaining a healthy mood, vagus
nerve stimulation may be an option for depression treatment.
Effects on mild depressive disorder
Untreated mild depressive disorder is one causative factor for major
depression and moderate psychosis. It is an unavoidable progression unless
mild depression events are healed effectively. Furthermore, patients with
mild depression are usually capable of answering drug treatment and other
remedies. Vagus nerve based therapies may be an optional remedy for mild
depressive disorders.
Mild depressive disorders are one of the most common forms of mental
disorders in society. Unfortunately, drug treatment of mild depressive
disorder sometimes cannot satisfy patients. Vagus nerve stimulation is a
relatively new and encouraging physical treatment for mild depressive
disorders. One of the advantages of vagus nerve stimulation based therapy
is explained as the long-term benefits in mood regulation. However,
because this intervention involves surgery, perioperative risks, and
potentially significant side effects, this method has been restricted to
patients with treatment-resistant depression. These patients have no
response to medication treatment.
BMC, a complementary and alternative medicine journal, published a
double-blinded randomized clinical trial that aimed to overcome limitations
of side/adverse effects by introducing a novel method. In this study,
clinicians stimulated superficial branches of the vagus nerve on the ear to
treat mild depressive disorder. The basis of this method was direct
stimulation of the afferent nerve fibers on the ear area with afferent vagus
nerve. To obtain a similar effect as classic vagus nerve stimulation, clinic
application procedures were performed without the burden of surgical
intervention. This study has the potential to extend the application of vagus
nerve stimulation treatment for depressive disorders and other disorders,
such as morbid obesity, bipolar disorder, and epilepsy, resulting in direct
benefit to the patients suffering from these highly widespread disorders. In
addition, the results of this double-blinded clinical trial can give inspiration
to consideration of acupuncture point specificity and development of
procedures in clinical trials of acupuncture cure3 . Studies indicate that
vagus nerve stimulation may provide long-term sustained benefits, which is
particularly compelling given the highly recurrent nature of mild depressive
disorder. However, the involvement of surgery, perioperative risks, and
potentially significant side effects have limited this treatment only to those
patients who have been treated for depression in the past but have failed to
respond to at least 4 prescribed medications and/or established somatic
treatment options such as electroconvulsive therapy for mild depressive
disorder. The double-blinded randomized clinical trial aims to overcome the
limitations of vagus nerve stimulation by testing the efficacy of a novel
method of transcutaneous vagus nerve stimulation to treat mild depression
disorder. The rationale for using vagus nerve stimulation is that anatomical
studies have shown that the ear is the only place on the surface of the
human body where there is different vagus nerve distribution. Thus, direct
stimulation of afferent nerve fibres on the ear should produce an effect
similar to classic vagus nerve stimulation in reducing depressive symptoms
without the burden of surgery intervention. Additionally, an important
branch of acupuncture has been widely used to treat various disorders
including mild depressive disorder by stimulating points on the ear.
Compared with traditional vagus nerve stimulation, transceutical vagus
nerve stimulation has advantages of being low cost, safe and non-invasive.

Effects on major depression

Major depression is the most commonly seen type of depression in humans,
especially women. Although several medications and plant materials have
been used for treatment of major depression, some people cannot be treated
definitively. Also, we sometimes can confront individuals who were treated
with an agent, but major depression reoccurs. Briefly, treatment of major
depression is very complicated and the success of healing can be subjective.
In addition to drug therapy, clinicians may also add supplementary
methods, such as enhancing social support, encouraging nutraceuticals, and
advocating vagus nerve based therapies.
In 2002, vagus nerve stimulation in major depressive individuals was
reported as promising. The study was conducted to determine whether the
initial promising effects were sustained and whether changes in function
would be observed. Thirty adult outpatients in a treatment-resistant,
nonpsychotic major depressive episode received an additional 9 months of
vagus nerve stimulation treatment following exit from the 3-month acute
study. Alterations in psychotropic medications and vagus nerve stimulation
parameters were detected during this longer-term follow-up study.
Scientists concluded that longer-term vagus nerve stimulation treatment was
associated with sustained symptomatic benefit and sustained or enhanced
functional status in this study.4, 5
The target population for vagus nerve stimulation is patients with unipolar
or bipolar major depression who have failed at least four adequate trials of
antidepressant medication and/or ECT . Consideration for its use should
also take into account that response may take 6 to 12 months. Hence,
patients who are actively suicidal or unable to care for themselves because
of depression or otherwise requiring a rapid response would not be good
candidates. There is also a wide range of responses to vagus nerve therapy.
The evidence from clinical trials suggests that, in addition to the third of
patients who meet the typical threshold of antidepressant response of a 50%
drop in a depression rating scale, another third may have a 25% to 50%
response.
At least 80,000 individuals (4000 for Treatment Resistant Depression,
remainder for refractory epilepsy) in 70 countries have been implanted with
vagus nerve stimulation until 2015. Considerable safety and tolerability
data were presented. As reported in 1999 from the experience with vagus
nerve stimulation for refractory epilepsy and confirmed by the subsequent
experience from multiple depression studies, most side effects are related to
the stimulation from the device or an extremely low risk of surgical
complication. The device is attached to the left vagus nerve just
below/distal to where the recurrent laryngeal nerve comes off the vagus.
Leakage of the afferent signal to the recurrent laryngeal frequently may
cause voice alteration while the device is delivering stimulation6 .
Clinical experience has demonstrated that some patients with only minimal
antidepressant response have requested to keep receiving vagus nerve based
therapy because they report no longer being suicidal and are better able to
enjoy some activities. Some may report that the worst they get is less severe
than it once was, that is, vagus nerve stimulation seems to "raise the floor"
on the severity of major depression .

The roles on anxiety

The term “anxiety” can be defined as our body’s natural response to
stressful conditions. It is a feeling of fear or worry about what’s to come.
What will I do, what is next? The first day of school, going to a job
interview, or attending a meeting may cause you to feel fearful and nervous.
Anxiety disorders are the other common type of emotional disorder and can
occur at any age: a student starting at primary school or an elderly person.
Adults can also feel irritable for a variety of reasons. The cause can be
divided into two general categories: physical and psychological. Several
common psychological causes of irritability include: stress, anxiety, and
autism. Some mental health disorders have been associated with irritability,
including: but not limited to: depression, bipolar disorder, and
schizophrenia. Common physical causes can include sleep deprivation, low
blood sugar, ear infections, toothaches, some diabetes-related symptoms,
certain respiratory disorders, and flu. Medical conditions that include
hormonal changes can also affect your mood. Examples include:
menopause, premenstrual syndrome, polycystic ovary syndrome,
hyperthyroidism, diabetes. Elderly people may also experience irritability
as a side effect of medication they are taking. According to the American
Psychiatric Association, women are more likely than men to be diagnosed
with an anxiety event. However, there are plenty of remedies for anxiety.
Drug therapy, sometimes relaxation techniques, or other methods can be
applied to get rid of anxiety. The treatment methods have a varying range.
When feelings of anxiety accumulate and get extreme, last longer than six
months, and are interfering with your life, you should search for a remedy
for the current anxiety disorder. As discussed, vagus nerve stimulation is an
effective therapy for chronic resistant depression. Because these disorders’
mechanisms of action are similar, vagus nerve based methods can be
applied for anxiety disorder.
The vagus nerve sends information to brain regions (locus coeruleus,
orbitofrontal cortex, insula, hippocampus and amygdala ) that have a vital
role in anxiety regulation. This pathway might be involved in perceiving or
manifesting various somatic and cognitive symptoms that characterize
anxiety disorders. On the basis of this reasoning and reports of anxiolytic
effects of vagus nerve stimulation in patients treated for epilepsy and
depression, clinicians have organized an open-label pilot acute trial. Eleven
adult outpatients with treatment resistant obsessive-compulsive disorder,
panic disorder, or posttraumatic stress disorder were enrolled in this study.
All patients were rated with the Hamilton Anxiety Scale and the clinical
global impressions improvement scale. Alterations in medications and
vagus nerve stimulation parameters were allowed during the long-term
follow-up. The result of this study supposed toleration with vagus nerve
stimulation. These data suggest that further double-blind studies assessing
the vagus nerve stimulation role in treating anxiety disorders, particularly
obsessive compulsive disorder, may be necessary.7
Melanie Klarer et al. reported innate anxiety and learned fear are both
subjected to visceral modulation through abdominal vagal afferents on rats.
These preclinical data have suggested theories emphasizing an important
role of afferent visceral signals in the regulation of emotional behavior.
Moreover, the emergence of attenuated fear extinction after sub
diaphragmatic vagal differentiation further highlights the importance of
vagal afferent signaling for the remission of learned fear, which may endure
clinical relevance especially to the pathophysiology of post traumatic
disorder and related disorders 8 .
An emerging question that awaits exploration is whether the behavioral and
neurochemical consequences of surgical sub diaphragmatic vagal
deafferentiation may reflect a failure of the organism to convey gut-derived
signals from the viscera to the central nervous system. This surgical
technique consists in the left-side intracranial transection from the vagal
afferent rootlets and ipsilateral transection of the dorsal subdiaphragmatic
trunk of the vagus nerve resulting in complete subdiaphragmatic
deafferentation. It is the most complete and selective vagal deafferentation
method existing to date, to study the consequences of abdominal vagal
afferents on innate anxiety, conditioned fear, and neurochemical parameters
in the limbic system. This hypothesis is particularly interesting in view of
the findings demonstrating that germ-free mice lacking commensal gut-
associated bacteria or mice receiving probiotic treatment with
Lactobacillusrhamnosus show reduced innate anxiety-related behavior 9 .
An alternative (but not mutually exclusive) mechanism may be that the sub
traumatic vagal differentiation induced effects on emotional behavior and
neurochemistry may be associated with functional alterations in the
sympathetic nervous system. Future investigations of the possible links
between sub traumatic vagal differentiations, gut derived signals, and/or
sympathetic functions will readily help to obtain more in-depth insights,
whereby visceral signals can influence complex brain and behavioral
functions.

The link between Yoga and vagus nerve

A theory proposed to explain the benefits of yoga practices has been argued
for many years. Yoga practices may reduce dynamic energy load in stress
response systems. It is asserted that endurance of optimal homeostasis can
be restored with yoga. As it is known, stress affects imbalance of the
autonomic nervous system. When we confront a stressful situation, the
parasympathetic nervous system activity decreases and sympathetic nervous
system activity increases.

The effects of yoga can touch psychological conditions, including anxiety,

depression, pain patterns, cardiovascular disorders, immune system, and
pregnancy. Furthermore, the physiological effects of yoga, including
decreased heart rate and blood pressure, and the physical effects, including
weight loss and increased muscle strength, are the other ones. Finally,
potential underlying mechanisms suggest that stimulation of pressure
receptors lead to enhanced vagal activity and reduced cortisol . The
reduction in cortisol levels may contribute to the positive effects of yoga,
such as enhanced immune function and a lower prematurity rate. 10
 The relation
between yoga and the vagus nerve will be discussed extensively in section
12 under the headline of meditation.
To better understand how to perform the yoga poses, I suggest you consult
our video course attached to the book.
Here is the link:
Https://Emma.wisementorpress.com/Course1
The first 5 days mainly focus on that part of yoga, so I highly recommend
it.
Key Points in one page
The FDA has correspondingly approved vagus nerve
stimulation for the treatment of depression in adults who have
chronic and treatment-resistant depression.

Clinicians have reported in a double-blind randomized clinical

trial that stimulation of the vagus nerve can treat mild
depressive disorder.

At least 80,000 individuals (4000 for treatment-resistant

depression, the remainder for refractory epilepsy) in 70
countries have been implanted with vagus nerve stimulation
by 2015.

Preclinical studies have reported that innate anxiety and

learned fear are both linked with abdominal vagal afferent
nerves.
When we confront a stressful situation, parasympathetic
nervous system activity decreases and sympathetic nervous
system activity increases. Yoga can be a solution to combat
stressful circumstances.
 SECTION 7: AN OPTIONAL
REMEDY FOR POST
TRAUMATIC STRESS
DISORDER
Relation with vagus nerve and posttraumatic stress
disorder

Posttraumatic stress disorder is one

anxiety disorder that can develop after trauma. Some characteristic features
of this disease are experiencing foggy memory, hallucinations,
hypervigilance, nightmares, social avoidance, and other specific social
dysfunctions. The symptoms of post-traumatic stress disorder can also be
defined as avoidance behavior, cognitive and affective alterations, and
changes in arousal and reactivity. Patients who suffer from post-traumatic
stress disorder usually tend to live as though under a permanent threat. They
display fight and flight behavior and dissociation, with no possibility of
reaching a calm state and developing confident social communications. As
a result of these responses, patients can be under risk for psychiatric
comorbidities, such as drug addiction and cardiovascular diseases.

Symptoms of posttraumatic stress disorder are partially relevant with the

vagus nerve. Reduced parasympathetic activity in post-traumatic stress
disorder is also related to an autonomic imbalance. The vagal control of
heart rate via the vagal fibers varies with lung capacity and breathing.
Therefore, the vagal influence on the heart can be evaluated by measuring
the amplitude of rhythmic fluctuations in heart rate. Additionally, patients
with post-traumatic stress disorder have lower high-frequency heart rate
variability than healthy individuals.
Stimulation of the vagus nerve can be an option in treatment-resistant
anxiety disorders, including post-traumatic stress disorder. Chronic vagus
nerve stimulation has been shown to reduce anxiety in animal studies. In
addition, an improvement has been detected on the Hamilton Anxiety Scale
in a human study that was performed on treatment-resistant depression. 1
Vagus nerve stimulation increases the release of noradrenaline in the region
of the brain's basolateral amygdala as well as the hippocampus and cortex.
Noradrenaline has a fundamental role in the amygdala for a better learning
process. Thus, vagus nerve stimulation could be a good approach to
increase extinction retention. For example, in rats, extinction paired with
vagus nerve stimulation treatment can help in the remission of fear and
improvements in post-traumatic stress disorder symptoms. Additionally,
vagus nerve stimulation may also enhance extinction by inhibiting activity
of the sympathetic nervous system.2
In 2001, scientists from the USA and Israel reported that trauma survivors
who develop post-traumatic stress disorder differ from those who do not to
the extent to which their heart rate response to challenge is controlled by
vagal activity. Responses to challenge in post-traumatic stress disorder may
be facilitated by the non-vagal pathway and mediated by sympathetic
mechanisms. This study was performed with 15 patients with post-
traumatic disorder and 14 without. Individuals with post-traumatic stress
disorder (PTSD) demonstrate hyperactivity of the sympathetic branch of the
autonomic nervous system, as evidenced by changes in the heart rate, blood
pressure, skin conductance level, and other psychophysiological measures.
They also have elevated noradrenergic reactivity to pharmacological
challenges. A variety of other neurotransmitter systems, such as the
serotonin, GABA, glumate, neuropetide Y, and endogenous opioids, show
altered functioning in individuals with PTSD. Complex PTSD often leads to
poor resilience, increased risk of depressive and anxiety disorder, and
increased somatization. Numerous situations will trigger these individuals
and lead to very strong adverse emotional reactions. Veterans with combat-
related PTSD displayed significantly depressed heart rate variability as
compared to subjects without PTSD.
It should be taken into account that there is a need for randomized
controlled trials to approve these observations. Emerging research suggests
that probiotics can have a potential to decrease stress-induced inflammatory
responses, as well as associated symptoms.
Studies performed in healthy volunteers have supposed that the
administration of particular probiotics are associated with an improved
well-being as well as a decrease in anxiety and psychological distress3 .
Can vagus nerve stimulation heal post traumatic
stress disorder?
The short answer is that it is too early to say vagus nerve stimulation can
heal post-traumatic stress disorder. But we can conclude that these
preliminary findings are giving an inspiration about the beneficial effect of
vagus nerve modulation on posttraumatic disorder. Finally, it would be a
great conclusion that there is an urgent necessity for well-designed, double-
blind, placebo-controlled clinical trials on vagus nerve based therapies on
post-traumatic disorder.
Vagus nerve stimulation works by applying electrical impulses to the vagus
nerve. The stimulation of the vagus nerve can be implemented in a direct
invasive stimulation, which is currently the most common application.
Another method is an indirect transcutaneous non-invasive stimulation.
Invasive vagus nerve stimulation (ivagus nerve stimulation) requires the
operating implantation of a small pulse generator subcutaneously in the left
thoracic region.
Electrodes are attached to the left cervical vagus nerve and are connected to
the pulse creator by a lead that is tunneled under the skin. The generator
transports intermittent electrical impulses through the vagus nerve to the
central nervous system. It is claimed that these electrical impulses exert
anti-depressive, anti-epileptic, and anti-inflammatory effects by altering the
excitability of nerve cells .
Transcutaneous vagus nerve stimulation allows for a non-invasive
stimulation of the vagus nerve without any surgical procedure in contrast to
invasive vagus nerve stimulation. At this point, the stimulator is generally
attached to the auricular concha via ear clips. Then, it produces electrical
impulses at the subcutaneous course of the afferent auricular branch of the
vagus nerve. A pilot study that tested the application of vagus nerve
stimulation in 60 patients with treatment-resistant depressive disorder
showed a significant clinical improvement in 30–37% of patients and a high
tolerability. The stimulation of the vagus nerve for the treatment of
refractory depression was approved by the U.S. Food and Drug
Administration. Since then, the safety and efficacy of vagus nerve
stimulation in depression has been demonstrated in numerous observational
studies as discussed in section 3. In contrast, more randomized, placebo-
control clinical trials are needed to confirm the antidepressant effects of
vagus nerve stimulation4-8 .
Key Points in one page
These results provide evidence that extinction paired with
vagus nerve stimulation treatment can lead to remission of
fear and improvements in post-traumatic stress disorder like
symptoms.
Preliminary findings are hopeful for a beneficial effect of
vagus nerve modulation in people with PTSD.
 SECTION 8: COGNITIVE
SKILLS CAN BE
IMPROVED BY PROPER
STIMULATION
Role of vagus nerve on cognition

The term “cognition”

can be generally defined as mental processes involved in gaining
knowledge and comprehension. These processes include thinking,
accounting, remembering, judging, and problem-solving. These are higher-
level functions of the brain and encompass language, imagination,
perception, and planning1 .
Accumulated data have shown that vagus nerve stimulation can facilitate
neuroplasticity and memory in animal models and human studies. Scientific
studies specifically investigated the short-term effect of VNS on cognitive
skills, including memory consolidation and retrieval processes, creativity,
cognitive flexibility, and decision making. To understand VNS’s effect on
cognition, experimental sessions consisted of two blocks separated by a
break. In each block, seven narrative paragraphs were presented to the
participants to read out loud: one practice paragraph and six experimental
paragraphs. In each block, three of the experimental paragraphs contained
highlighted words. In one of the blocks, the reading of the paragraphs with
the highlighted words was followed by 30 s of VNS (30 Hz; 0.5 ms). In the
other block, the reading of the paragraphs with the highlighted words was
followed by sham stimulation (0.0 mA). Patients were asked to recall the
highlighted words immediately after true or sham stimulation was
delivered. Based on the results of this experiment, the researchers
concluded that VNS, administered during memory consolidation, causes
intensity-dependent enhancement of word recognition performance. They
theorized the memory enhancing effect is an inverted U-shape function of
the current intensity of VNS 2 .
In 2001, another experimental study was performed by Helmstaedter et al.
Memory and decision time were experimentally tested in a within-subject
box-car design using a computerized memory task. Eleven patients had to
memorize lists of 15 words and 9 figures during three learning trials,
immediately followed by the recognition of the target trials between twice
as many distractors.
VNS was applied the entire time (i.e., 4.5 m) during learning and recall with
a current intensity of >1 mA (mean of 1.75 mA according to personal
therapeutic tolerance level, 0.5 ms, 30 Hz). For evaluation of the
performance, normative data from three repeating tests were collected in 20
healthy subjects.
The researchers reported a significant, fully reversible deterioration of
figural recognition memory when high intensity VNS was delivered during
learning and retrieval processes. However, the decision times for
recognition of the verbal target items showed a significant acceleration
during VNS and reduced to baseline level after stimulation, suggesting a
positive effect of VNS on attention and arousal 3 .
These two clinical studies2 , 3 showed memory enhancement with VNS
(stimulation administered at intensities between 0.75 and 1.5 mA). When
we evaluate these studies and others, the effect of short-term VNS on
recognition and recall performance (when VNS was administered after
receiving information) suggests VNS has an effect on the processes of
memory consolidation.
Additionally, it is clearly seen that the effects of VNS in controlled study
conditions appear to be time and dose-dependent. Translating the
application of VNS to clinical practice may be challenging. This would
mean the vagus nerve needs activation at a current of 0.50 mA each time
information is being consolidated. When we take this into account, we can
assume the results of previous studies have a rather theoretical meaning.
Considering the vagal–brain interaction at the moment of measurement may
provide clinical relevance.
The other important issue is the relationship with memory and epigenetic
mechanisms. Researchers have tried to identify an epigenetic code or
histone code that can be related with VNS. There is new scientific data
supposing the association between epigenetic modulators and synaptic
plasticity, learning, and memory 4 . Epigenetic effects and the underlying
modulation of transcription and translation have been identified by
researchers. For example, the histone modification H3K4me3
(trimethylation of histone H3 on lysine 4) is known to be associated with
increased transcriptional activation5 (a protein that increases gene
transcription of a gene or set of genes. Most activators are DNA-binding
proteins that bind to enhancers or promoter-proximal elements. Most
activators function by binding a sequence specifically to a DNA site located
in or near a promoter and making protein-protein interactions with the
general transcription machinery thereby facilitating the binding of the
general transcription machinery to the promoter.
A decreased level of NFκB1 in the cortex and blood, along with inversely
correlated hippocampal NFκB1 and cognitive performance, revealed a
widespread VNS effect on stress–response signaling. VNS-induced
reductions in NFκB1 relating to cytokine level, such as reduced TNF, have
been reported. However, the minimal change in cytokine transcription in the
hippocampus and cortex in rats proposes that NFκB1 effects in these
structures could be related to alternative stress–response modulators, such
as hormones and histone modifiers.
VNS-induced epigenetic and transcriptome modifications have been
associated with improved cognition, reduced stress–response signaling,
cortical synaptic plasticity, calcium signaling changes, and increased
hippocampal output. Taken together, this evidence can suggest that VNS
enhances novelty preference during a multiday object contact task. Also,
investigation of whether epigenetic mechanisms underlie the enhancement
would be valuable for future aspects of vagus nerve based therapies.
In 2014, a group of scientists reviewed the data of vagus nerve stimulation
on cognitive skills. They listed 10 epilepsy studies, 2 Alzheimer’s disease
studies, and 1 depression event study. The patients were treated with this
method in long-term and short-term treatments. When we look at the
reviewed results, main findings are hopeful for advanced new studies 6 .
For improved memory
Human memory implicates the ability either to preserve or recover
information that we have learned. As we all know, memorization is not a
flawless process; sometimes we forget or misremember things or events. To
decide whether we have memory problems, a clinician should test via the
scientific parameters. Memory refers to the processes used to acquire, store,
retain, and later retrieve information. Augmentation of disrupted memory or
getting an improved memory is so complicated, and numerous factors play
a role in this process.
Imbalanced immunity is one of the main hallmarks of several disease states
and is an attractive target to treat or delay the onset of different conditions,
including neurological disorders. The nervous system plays key roles in the
regulation of immunity and inflammatory challenges, sending signals via
afferent neurons as well as the vagus nerve. Vagal signaling is crucial to the
immune-response mechanism. Recently, electrical vagal nerve stimulation
was applied as an alternative therapy in patients with autoimmune disorders
to inhibit tumor necrosis factor-a (TNF-a), one of the key inflammatory
targets in rheumatoid arthritis and other disorders. Neuroinflammation has
been labelled as a critical influence of cognitive deficits, and glia cells play
a role in this process primarily.
Researchers from the USA have established a novel procedure for
stimulating the vagus nerve using a minimally invasive percutaneous needle
approach in mice. They concluded VNS showed a decrement on systemic
inflammation and alteration in microglia morphology. These results have
encouraged us to provide a novel therapeutic approach, using bioelectronic
medicine to modulate a neuroimmune effect on cognitive skills. In
conclusion, we should point out that advanced human studies are needed to
define the mechanisms whereby VNS regulates its neuroprotective effects,
including changes in microgliaactivity, neuroinflammation, neuronal
signaling, and behavior 7 .
Effects on neurological diseases
Vagus nerve stimulation has emerged as an optional treatment for patients
with refractory epilepsy, based on the clinical observation of improved
cognition in many epilepsy patients who get VNS. The recent literature
shows evidence regarding the cognitive effects of this treatment. As we
understand from most of the studies, with currently used stimulation
parameters, the effects on memory are only of theoretical importance.
However, some animal studies have suggested hopeful effects on specific
modalities of memory function. Preliminary results of VNS in the treatment
of neurological diseases related with cognitive decline such as Alzheimer’s
disease seem promising but need to be further investigated. In studies of
epilepsy patients, there is no evidence of adverse effects on cognitive
abilities, but clear-cut positive effects cannot be expected either.
When we collect and gather the scientific data, numerous logical reasons
are occurring to assume an effect of VNS on cognition. As discussed, the
nucleus of the solitary tract in the brain stem is the main transmit station for
afferent vagal nerve fibers. This nucleus has wide range projections to
numerous areas in the forebrain, as well as the brain stem, including areas
involved in learning and memory formation. The Amygdala and
hippocampus are the regions of the central nervous system that we can
think of in this context.
Stimulation of the vagus nerve can initiate some alterations in the
electrophysiological and metabolic profile of brain structures. It is apparent
from studies that VNS has improved cognition. Furthermore, it is believed
that some neurotransmitters have an effect on stimulation of learning and
memory, which exerts their effect through activation of peripheral receptors
that send neural information to the central nervous system through the
vagus nerve.
Clark et al. researched affective memory with a one-trial inhibitory-
avoidance task in animals. They applied post-training vagus nerve
stimulation (stimulation parameters: 500 ms, 20 Hz, 30 s) to rats and
compared the results with non-treated animals. The inhibitory-avoidance
task consisted of an electrical foot shock administered when the animal
enters a darkened room. Retention to enter the darkened room was tested 24
h later. There was a significantly improved retention performance in rats 8 .
Bipolar disorder
Bipolar disorder is characterized by periods of major depression that
alternate with periods of mania (typified by elevated or irritable mood,
increased energy, reduced need to sleep, exaggerated self-importance,
thoughtless behavior, and thought troubles). Bipolar disorder is a
heterogeneous set of illnesses and its subtypes are categorized as bipolar 1
disorder and bipolar 2 disorder. Bipolar 1 disorder is defined as the presence
of at least one or more episodes of mania with a period of at least one week
that may occur in the presence or absence of major depression. Bipolar 2
disorder is defined as the presence of at least one or more episodes of
hypomania escorted by at least one episode of major depression without
psychotic features.
The precise cause of bipolar disorder is not fully understood, but there are
some contributing factors that can be listed as genetic influences,
environmental factors linked to stress, biochemical factors that include
changes in neurotransmitter concentrations in the brain and hormonal
alterations, and neurophysiological factors that comprise changes in specific
neural networks in the brain.
Vagus nerve stimulation seems to be an optional treatment for patients with
treatment-resistant unipolar and bipolar depression. The outcome of vagus
nerve stimulation for patients with bipolar treatment-resistant depression
has been researched in the Massachusetts General Hospital. This study
describes the outcome of VNS effect for bipolar treatment-resistant
depression patients participating in the acute and long-term treatment. Also,
they compared the data with unipolar treatment-resistant depression patients
in the same trials. VNS short- and longitude effects on bipolar and unipolar
treatment-resistant depression were similar. However, the findings should
not be interpreted as warranting clinical inference regarding effectiveness of
VNS in patients with bipolar depression 9 .
Another clinical trial was conducted on vagus nerve stimulation in
treatment-resistant, rapid-cycling bipolar disorder for 12 months.
Researchers reported that VNS was associated with a 38.1% mean
improvement in overall illness as compared to baseline, as well as
significant reductions in symptoms as measured by the HAM-D-24
(Hamilton Rating Scale for Depression), MADRS (Montgomery-Asberg
Depression Rating Scale), CGI (Clinical Global Impressions), and GAF
(Global Assessment of Functioning) evaluation scales. However, clinicians
also warned about the common adverse events they confronted, such as
voice alteration and hoarseness10 .
Anxiety disorders
Experiencing random anxiety is a normal part of life. But, people with
anxiety disorders frequently have forceful, excessive, and persistent anxiety
and worry about everyday situations. Often, anxiety disorders involve
repeated episodes of sudden feelings of intense anxiety and fear or terror
that spread, with a peak within minutes, resulting in panic attacks.
These feelings of anxiety and panic that affect daily activities are hard to
control and may be an actual danger when it lasts for a long time. People
with severe anxiety may excessively avoid places or situations to preserve
themselves from these feelings. Indications can be seen during childhood or
the teen years and continue into later life. Generalized anxiety disorder,
social anxiety disorder (also named as social phobia), specific phobias, and
separation anxiety disorder are the most seen anxiety types. The assessment
of anxiety level should be performed by a psychiatrist who would decide if
treatment is needed. It should be kept in mind that every anxiety is not
malign; however, some worry/fear may sometimes help us to succeed or
avoid unwanted situations.
There is evidence that vagal afferent signaling has been involved to control
mood and mental skills, including particular forms of anxiety and fear.
However, relative involvement of vagal afferent nerves versus vagal
efferent nerves in the modulation of emotional functions remains obscure.
One study demonstrated that innate anxiety and learned fear are both
exposed to visceral modulation through abdominal vagal afferents, possibly
via altering limbic neurotransmitter systems. These data suggested an
important role of afferent visceral signals in the regulation of emotional
behavior in animals. The behavioral and neurochemical consequences of
subdiaphragmatic vagal differentiation may reflect a failure of the organism
to transport gut-derived signals to the central nervous system11 .
The effects of vagus nerve stimulation in humans were monitored in a
double blind clinical study for 12 weeks. Eleven patients were recruited in
this study (7 obsessive-compulsive disorder, 2 posttraumatic stress disorder,
and 1 panic disorder). Results were documented as 50% improvement on
the Hamilton Anxiety Scale for all patients. In addition, 25% improvement
on the Yale-Brown Obsessive Compulsive Scale was seen in patients with
obsessive compulsive disorder.
Treatment-resistant anxiety disorders can be listed as life threatening
diseases that cause problems in social life and business. VNS treatment is a
hopeful option for these severe anxiety pathologies. Maybe further double-
blind studies can assess the VNS role in treating anxiety disorders,
particularly obsessive-compulsive disorder.
Alzheimer's disease
Alzheimer’s disease accounts for the majority of cases of dementia, and in
recent years, much effort has been expended in trying to understand the
underlying mechanisms involved in its pathophysiology with a view to
treating and reducing the progression of this disease. New pharmacological
and non-pharmacological strategies, based on our present understanding of
the pathophysiological and neurochemical changes that occur during the
progression of the disease are currently under preclinical and clinical
investigation. We hope it is likely that, in the next decade, novel therapies
may become available to treat Alzheimer’s disease more successfully.
In 1901, Alois Alzheimer admitted a 51-year-old female known as Auguste
D to the Municipal Institute in Frankfurt, Germany. She was suffering from
a type of presenile dementia characterized by progressive memory loss and
auditory and visual hallucinations. Dr. Alzheimer detected and recorded the
nature of the disease for the five years until Auguste’s death in April 1906.
Alzheimer described the clinical and neuropathological characteristics of
the disease and published them in 1907. Alzheimer’s description of the
progression of his patient’s condition is given below.
““A woman, 51 years old, showed jealousy towards her
husband as the first noticeable sign of the disease. Soon a
rapidly increasing loss of memory could be noticed. She
could not find her way around in her own apartment. She
carried objects back and forth and hid them. At times she
would think that someone wanted to kill her and would begin
shrieking loudly. In the institution her behaviour bore the
stamp of utter perplexity…
Periodically she was totally delirious, dragged her bedding
around, called her husband and her daughter, and seemed to
have auditory hallucinations.
…“The generalised dementia progressed however…After 4
years of the disease, death occurred. At the end, the patient
was completely stuporose; she lay in her bed with her legs
drawn up under her…””
Alzheimer’s disease can be considered a cortical dementia because many
cognitive functions attributed to normal operation of the cortex, especially
those ascribed to cortical association areas, become impaired. Thus, many
functions related with the areas in the cortex are affected by Alzheimer’s
disease, including learning and memory, language, constructional skills and
visual, auditory and spatial perception. However, other areas of the brain
are also affected by Alzheimer’s disease, with memory loss additionally
reflecting hippocampal involvement and the anxiety, depression and
personality changes that often accompany the disease linking limbic
structures .
The clinical symptoms of Alzheimer’s disease can be complex and
dependent on age of onset, education, social isolation, exercise, and diet.
More importantly, some disorders, such as diabetes, hypertension ,
cardiovascular events, anxiety and depression, can be related to the
progression of Alzheimer’s disease. However, the majority of patients will
display most of these disorder symptoms described here as the disease
progresses.
Calculated life expectancy of patients diagnosed with Alzheimer’s disease
will also vary with age. Younger patients in their mid-60s–70s can expect to
live, on average, for 8–10 years after the symptoms of the condition are
diagnosed, whereas elderly people with Alzheimer’s disease in their mid-
80s will probably live for about 3–5 years.
Alzheimer’s disease pathology is described by the accumulation of β-
amyloid plaques (contains aggregated amyloid) and over regulated
neurofibrillary tangles (contains hyperphosphorylated tau protein) in the
cerebral cortex and subcortical areas. These biomarkers can be detected in
the cerebrospinal fluid and indicate disease severity and progression. The
findings of elevated tau-protein levels and β-amyloid levels in the CSF are
the main markers of Alzheimer’s disease.
Merrill et al. performed a clinical study on patients with Alzheimer's
disease to investigate any effects of VNS. The results of the study showed
that approximately 70% of the patients experienced an enhancement on the
cognitive screening after six months of stimulation; also, absence in decline
was detected in some patients. Nevertheless, this improvement decreased to
40% after one year of treatment. The authors supposed that the early
improvement was eventually followed by a gradual but delayed decline,
representing a delayed progression of Alzheimer's disease. Alzheimer's
disease Assessment Scale-cognitive subscale (ADAS-cog) and Mini-Mental
State Examination (MMSE) were measured to determine any improvement
or absence of decline from baseline. In addition, overall change in
participant’s mood, depressive symptoms, and quality of life were also
evaluated.
Moreover, clinicians researched advanced biochemical parameters to assess
any alteration with VNS. Cerebrospinal fluid levels of total tau,
phosphorylated tau (Thr181) and β-amyloid protein (Aβ42) were measured
by standardized enzyme-linked immunosorbent assay. When we look at the
results of this study, 41.2% and 70.6% of patients showed an improvement
or did not decline from baseline in the evaluation of the ADAS-cog and
MMSE, respectively. Whereas, 70.6% of patients were rated as having no
change or some improvement from baseline in the evaluation of the
Clinician Interview-Based Impression of Change (CIBIC+). Also, it was
declared that VNS was well-tolerated. Collectively, we can think that,
although alterations in biochemical parameters and other evaluations have a
positive outline, it should be kept in mind that VNS treatment does not
purely improve the cognitive symptoms in Alzheimer's disease. However,
effects of VNS in the underlying disease pathology are valuable results for
Alzheimer's disease 12 .
Key Points in one page
Accumulated scientific data proposed that vagus nerve
stimulation can facilitate neuroplasticity and memory in
animal models and human studies.

Though a few data asserted the beneficial effect of vagus

nerve stimulation, advanced human studies are needed to
define the mechanisms whereby the vagus nerve regulates its
neuroprotective effects, including changes in microglia
activity, neuroinflammation, and neuronal signaling pathways.

Stimulation of the vagus nerve can alter the

electrophysiological and metabolic profile of brain structures.

Vagus nerve stimulation is associated with a 38.1% mean

improvement in bipolar disorder. Significant reductions in
symptoms were detected by the HAM-D-24 (Hamilton Rating
Scale for Depression), MADRS (Montgomery-Asberg
Depression Rating Scale), CGI (Clinical Global Impressions),
and GAF (Global Assessment of Functioning) evaluation
scales.

Scientific evidence supposes that vagal afferent signaling has

been involved to control mood and mental skills, including
particular forms of anxiety and fear.
Merrill et al. reported that vagus nerve stimulation has positive
effects in patients with Alzheimer's disease. Approximately
70% of the patients exposed showed an enhancement on the
cognitive screening after six months of implantation of the
stimulation device by a comprehensive neuropsychological
assessment battery comprising tests on attention, motor
functioning, short-term memory, learning and memory, and
executive functions.
 SECTION 9: A HEALTHY
RESPIRATORY SYSTEM
Vagus nerve stimulation with respiratory system
The vagus nerve is one of the main regulators in normal physiological lung
functioning. As it is known, the lung expands during normal shallow
breathing, evoking vagus nerve activity. The evoked vagus nerve conducts a
message to the brain to constrict the bronchi, making breathing more
difficult. That's actually one explanation of why deep breathing is
necessary. Either deep inhalation needs deep exhalation, or this process
repeats subsequently as a result of the brain’s instruction via the vagus
nerve1 , 2 .
For many decades, yogis and sages from eastern nations have agreed on the
status of diaphragmatic breathing for well-being throughout life. From the
1970s, the mind-body thought thinkers have popularized the paramount
importance of deep breathing as a central component of keeping a healthy
physiological balance within the autonomic nervous system. Also, because
physiological balance is strongly related with hemostasis of the human
body, the importance of optimal stimulation and true ventilation of our
lungs can be understood.
Effective breathing to introduce vagal activity is mainly performed by
people who are more relaxed and can have self-confident speech. Oxygen
replacement in the respiratory system increases, due to filling up the lower
part of the lungs with fresh air. Some people practice diaphragmatic
breathing every day as a lifestyle, as part of a yoga or mindfulness-
meditation routine. Others only take a deep breath when they catch
themselves feeling anxious, need a break from stress, or want to relieve
some obstruction. Whether in a stressful position, or continuing life
normally, breathing deeply and slowly has been used for better body
condition. However, it should be kept in mind that extremely excessive
deep breathing can cause unexpected situations, such as syncope and
blackout.
Various diaphragmatic breathing techniques have emerged in the last few
years. Inhaling and exhaling only via mouth breathing is one of them.
Whereas some experts recommend breathing only through the nose and
then exhaling via mouth, this one is most famous and healthier in my view
because our nose is more successful than the mouth in keeping out
unwanted substances 3 , 4 .
Rhythmic and diaphragmatic breathing

Breathing
techniques are widely used in a variety of disorders, such as hypertension
and pulmonary diseases, as well as psychiatric disorders, including anxious
and depressive syndromes or stress-related disorders. With regard to
chronic pain syndromes, breathing methods as part of many physical,
mental, and spiritual disciplines such as yoga, Qi-Gong, and Tai Chi are
included in novel treatment approaches5 , 6 .

Several human studies have demonstrated the relationship between

diaphragmatic breathing and relaxing. The term relaxing represents a wide
range of effects such as decreased stress, mental and physiological comfort,
relief from nervous tension, and less tenseness or rigidity. We can
summarily suppose that the term of relaxation is opposite to stress. As it is
known, stress may cause various defects in our body from cancer to mental
disorders .
Stress induced oxidative stress can increase the glucocorticoid level in the
human body. In fact, there is proof to suggest that glucocorticoids induce
oxidative stress by changing the expression and activity of antioxidant
enzymes. Therefore, impairing the antioxidant defense of the body affects
essentially from stress. High levels of glucocorticoids are known to
decrease the substances responsible for fighting stress related disruptions.
Melatonin is one hormone made by the pineal gland to help control the
body’s sleep cycle and is an antioxidant. Melatonin exerts a direct
antioxidant effect on tissue/organs and antiapoptotic effects on biological
and physiological processes including alterations in metabolic, endocrine,
and immune pathways that lead to health problems involving obesity,
diabetes, hypertension, and respiratory diseases. Melatonin controls various
physiologic processes including circadian rhythms, mood regulation, and
cardiac function. Disturbances in circadian rhythm have been linked to
chronic diseases such as insomnia, hypertension, diabetes, and depression.
Recent studies investigated the age-related changes in cortisol and
melatonin rhythms and then presented descriptive statistics on preliminary
findings on the rectification of the cortisol rhythms by melatonin therapy.
Administration of exogenous melatonin around dusk will shift the phase of
human circadian clock to early hours (advance phase shift) leading to phase
advances in circadian rhythms (e.g sleep, endogenous melatonin, cortisol).
Support of circadian pacemaker function by melatonin may provide a new
strategy in the treatment of disorders related to impairments in the internal
temporal order. The clinical benefit from a decrease in cortisol during the
early part of the night may lie beyond the improvement of the sleep into a
better control of blood pressure, metabolism, and mood.
In fact, beyond its psychological and social effects, clinical studies have
documented that optimum breathing methods can improve the immune
system and its related functions.
There are also some psychological procedures, such as self-hypnosis in the
form of autogenic training, which have been proposed for healing certain
disorders such as hypertension and some cardiovascular events. In view of
the overwhelming evidence of the circadian stage dependence of any
treatment effects, the circadian stage depends on the effects of
diaphragmatic breathing .

Diaphragmatic breathing
is also referred to as slow abdominal breathing, something that can be done
to stimulate the vagus nerve and lower stress responses related with
parasympathetic nervous system activation. Diaphragmatic and deep
breathing furthermore improves heart rate variability, which is under control
of bidirectional relation with relax/digest action.
Considering that diaphragmatic breathing has a relaxing and therapeutic
effect on the human body, it is also recognized as a fundamental procedure
of Pranayama Yoga, Zen, transcendental meditation and other meditation
practices. Individuals who continue regular meditation have lower oxidative
stress levels, lower cortisol levels, and higher melatonin levels. It is
correspondingly emphasized that cortisol (glucocorticoids) inhibits
enzymes responsible for the antioxidant activity of cells and that melatonin
is a strong antioxidant.
 The 4-7-8
breathing technique, also known as relaxing breath, includes breathing in
for 4 seconds, holding the breath for 7 seconds, and exhaling for 8 seconds.
The aim of this breathing pattern is to reduce anxiety or help people to
relax. Likewise, some experts suppose the 4-7-8 breathing technique helps
persons get to sleep. Dr. Andrew Weil, a celebrity doctor and director of the
University of Arizona Center for Integrative Medicine, clarifies the 4-7-8
breathing technique, which he believes can help reduce anxiety, help a
person get to sleep, manage cravings, and control or reduce anger
responses. There is limited scientific research to support this method, but
there is a lot of anecdotal evidence to suggest that this type of deep,
rhythmic breathing is relaxing and may help ease people into sleep.
In 2009, Italian clinicians monitored 16 athletes during an exhaustive
training session. After the exercise, athletes were divided into two groups.
Participants of the studied group spent 1 h relaxing, performing
diaphragmatic breathing and concentrating on their breath in a quiet place.
The other group, the control group, spent the same time simply sitting in an
equivalent quiet place. Demonstrated results indicated that relaxation
induced by diaphragmatic breathing increases the antioxidant defense status
in athletes after in-depth exercise. These effects also correlate with
decrement of cortisol and increment of melatonin levels. The scientists
concluded there were lowered levels of oxidative stress, which suggests that
an appropriate diaphragmatic breathing could protect athletes from long-
term adverse effects of free radicals7 .
In conclusion, it is apparently understood that investigations of the effects
of diaphragmatic breathing on exercise-induced oxidative stress and the
putative role of cortisol and melatonin hormones in the stress process have
been studied further in the last years. However, further human based studies
performed on more participants and multicenter are needed to decide the
effects of breathing on stress and its related outcomes. Finally, it should be
remembered that a standardized and confirmed breathing process must be
defined by clinicians to reach successive results.

Using breathing to reduce pain

Deep and slow breathing methods, as a component of various relaxation
techniques, have been reported as complementary approaches in the
treatment of chronic pain syndromes. In this context, relaxation may play an
essential role in transforming breathing techniques into an effective method
in the therapy of pain and stress-related disorders. Moreover, breathing
deeply in concert with relaxation has been established to reduce stress-
linked biological activity. Besides, sustained concentration on inhaling and
exhaling during attentive breathing interventions has demonstrated an
increase in sympathetic arousal.
Relaxation may constitute a clinically effective component of breathing
methods, influencing mood processing. This aspect seems of importance,
considering that breathing management is able to modulate emotional
processing in the presence of pain, thus the mutual relationship between
pain and inhalation/exhalation emerges. However, the relevance of
relaxation for alleviating pain during a breathing intervention was not
evaluated comprehensively in recent studies.
Key Points in one page
Proper maintenance of physiological lung functions is tightly
related with vagal tone. Also effective breathing introduces
vagal activity, mainly performed by some people who are
more relaxed and have self-confident speech.

Different breathing techniques are used in a variety of

disorders, such as hypertension and pulmonary diseases, as
well as psychiatric disorders, including anxiety and depressive
syndromes or stress-related disorders.
Management of true breathing plays a role in the pain process,
but the mutual relationship between pain and
inhalation/exhalation is still under research.
 SECTION 10: RELAX WITH
DEEP BREATHING
Vagus nerve plays role in the respiratory system
Involuntary respiration is modulated by the respiratory centers of the upper
brainstem . Control of many involuntary and metabolic functions are
maintained in this region. The respiratory centers contain chemoreceptors
that sense pH (measure of hydrogen ion concentration) levels in the blood
and transport signals to the respiratory centers of the brain to regulate the
ventilation rate. As the result of alteration on breathing rate, acidity can be
optimized by increasing or decreasing the removal of carbon dioxide. As it
is known, CO2 level is one of the major parameters for hydrogen ions in the
blood. There are also chemoreceptors in other blood vessels that execute
ventilation rate as well.
We can say the vagus nerve is closely related with respiration. When
breathing deeply and slowly, the vagus nerve transmits a message to the
brain and the heart. For example, breathing slowly decreases the oxygen
demands of the heart muscle, and our heart rate slows down. In other
words, our body senses breathing and adapts its heart rate in response.
When we inhale, the sensory nodes on our lungs send a message up through
the vagus nerve and into the brain. Meanwhile, when we breathe out, the
brain sends a message back down through the vagus nerve to decrease or
increase the heart rate. In conclusion, breathing slowly causes bradycardia,
and we relax; breathing quickly triggers tachycardia and feeling anxious
and alarmed.
The vagus nerve innervates the diaphragm as well as regulates activities in
the larynx and pharynx. Vagus nerve activity is modulated by respiration. It
is suppressed when we breathe in and facilitated during exhalation, and the
vagus nerve down regulates respiration cycle frequency.
The styles of respiration are related with respiratory VNS, which are
controlled breathing techniques. Relaxed and deepened respiration and
stronger diaphragmatic breathing are the major substantial factors on the
vagus nerve. Respiratory VNS is bilateral stimulation by nature, as opposed
to unilateral electrical stimulation of the vagus nerve.
Heart rate changeability is dependent on inhalation and exhalation. Heart
rate increases on the inhale and falls on the exhale, and the difference
between those two rates are essentially actions of vagal tone. It is a well-
known example that athletes have higher vagal tone, while extended periods
of bed rest and astronauts in no-gravity situations have lower vagal tone.
Because some heavy drinkers have low vagal tone, vagus nerve stimulation
is discussed for an optional therapy for this kind of addiction.
As discussed, the parasympathetic nervous system and sympathetic nervous
system work conversely. This shift is known as vagal dominance. In vagal
dominance, chronic stress and stress-related conditions are weakened. As a
result of this situation, relaxation or rest and the digestion process are
regulated in our body.
Initiates body's relaxation response
Generally, it is complementary for relaying relaxation from the central
nervous system to the body and controlling the arousal and homeostatic
state of the viscera. Efferent vagus nerve fibers innervate the heart and the
lungs. The pulmonary efferent vagus nerve regulates airway magnitude and
its volume, so decreased respiration rate occurs and is indirectly affected by
endocrine secretion. Collectively, relaxation of the body is related with
either endocrinal substances or nerve innervation. Stress related endocrine
hormones and other substances have a major role in the cardiovascular and
respiratory system. So it can be concluded that bidirectional transfer is
working on relaxation of our body process.
Can optimal vagus nerve functioning improve
recovery rates after stress?
The vagus nerve is a two-way network between the brain and visceral
organs in our body. Maintaining its function properly is strongly related
with brain-body communication and results in a healthy body. We can
regulate our vagal pathways with breathing exercises, preserving gut
microbiota, and other easy practices. In addition, surgically-implanted
vagus nerve stimulators can help us to modulate vagus nerve functioning.
As mentioned, optimal vagus nerve modulation is mainly related with the
parameters listed below:

Central nervous system

Respiratory system
Cardiovascular system
Gastrointestinal system
Gut microbiota
Recovering after stress is associated with optimal immune system
regulation. Either excessive immune response or extremely low
immunomodulation are factors in our recovery after stress. We should keep
in mind that the vagus nerve can activate the immune system when we
combat any strange/dangerous microorganism or substance. Also, it is
clearly demonstrated in several scientific documents that immune system
activation is related with emotional mood. Clinicians use this knowledge for
therapy by stimulating the vagus nerve with electricity and pharmaceuticals
to treat immune system related disorders. Surgically implanted electric
vagus nerve stimulators in patients with severe epilepsy or depression have
also reported inflammatory response alterations 2 .
The action of vagus-nerve stimulation on inflammatory pathways is
explained as the acetylcholine and nicotine inhibition. Suppressing the
inflammation process is maintained by the cholinergic anti-inflammatory
pathway. These neurotransmitters inhibit the production of pro-
inflammatory cytokines from macrophages through a nicotinic anti-
inflammatory pathway dependent on the α7 nicotinic acetylcholine receptor
3
.
Recovering after stress is also associated with the respiratory and
cardiovascular system. Heart rate variability is an appropriate sign of acute
and chronic stress and can be used as an indirect indicator of vagus nerve
activity. This reflex is responsible for regulating blood pressure and is
triggered by stress-activated mechanoreceptors in vessels, which leads to
activation of the vagal branch of the heart node. Eventually, it reduces heart
rate and subsequently blood pressure down regulates.
The onset for triggering cardiovagal baroreflex sensitivity can be decreased
by a respiration rate around 0.1 Hz or about 6 breaths per minute.
Interestingly, this is exactly the same respiration rate reported in respiration
studies as having the highest increase of heart rate variability, dropping the
sensitivity results in more frequent reflexes, lower heart rate, and increased
vagal tone.
Key Points in one page
When we breathe deeply and slowly, the vagus nerve transmits
a message to the brain and heart. The respiration style is also
related with respiratory vagus nerve activation.

The pulmonary efferent vagus nerve regulates airway

magnitude and its volume.
Surgically implanted electric vagus nerve stimulators in
patients with severe epilepsy or depression have also reported
inflammatory response alterations. Also, heart rate variability
is an appropriate sign of acute and chronic stress and can be
used as an indirect indicator of vagus nerve activity.
 SECTION 11: THE
EFFICIENT RELAXATION
METHODS
As a new treatment approach: vagus nerve
stimulation
Epilepsy, diabetes mellitus, depression, anxiety, cardiovascular disorders,
migraine type headaches, and seizures are some of the chronic diseases that
can sometimes be treatment resistant. So clinicians and patients are
searching for alternative effective remedies to cure these disorders or
relieve symptoms at least.
Approximately one-third of people with epilepsy don't fully respond to anti-
seizure medications. Vagus nerve stimulation may be an option to reduce
the frequency of seizures in people who haven't achieved control with
medications. Vagus nerve stimulation may also be an option for patients
who haven't responded to intensive depression treatments, such as
antidepressant medications, psychotherapy, and electroconvulsive therapy.
Additionally, researchers are studying vagus nerve stimulation as a potential
treatment for a variety of conditions listed in the table.
Alzheimer's disease Gastrointestinal disorders
Anxiety disorder Inflammatory bowel
disease
Back and neck pain Rheumatoid arthritis
Bipolar disorder Cardiovascular disorders
Bulimia Respiratory system
 disorders
Obsessive-compulsive Migraine with aura
disorder
Morbid obesity Stomach ulcer
Major depression Mild cognitive disorders
The most common method for vagus nerve stimulation is a device to
stimulate the vagus nerve with electrical impulses. These methods are
generally applied by expert surgery clinicians. The FDA approved treating
epilepsy and depression with vagus nerve based methods. As we know, the
vagus nerve located on each side of our body is rooted from our brain stem
through the neck to the chest and abdomen. So, stimulation of the vagus
nerve is usually applied near the throat to stimulate inner organs of the
body.
The methods for vagus nerve stimulation are divergent. Conventionally, a
device is surgically implanted under the skin near the chest, and a wire is
put into the skin that connects the device to the vagus nerve. The device
conducts electrical signals along the left vagus nerve to the brainstem ,
consequently transporting signals into certain areas of the central nervous
system. In practice, the right vagus nerve is not stimulated for any treatment
purpose for any disorder. Clinicians know the right vagus nerve more
probably carries fibers to the innervation of the heart.
Novel methods are in progress for noninvasive vagus nerve stimulation. In
these methods, devices don't require surgical implantation. This method has
been permitted in Europe to treat epilepsy, depression, and pain. Also, a
noninvasive device that stimulates the vagus nerve has recently been
approved by the Food and Drug Administration for the treatment of
migraine headaches in the United States.
In 2015, a group of scientists evaluated the current evidence for the efficacy
and acceptability of vagus nerve stimulation when used as an adjunctive
treatment for individuals with medication-resistant epilepsy. Randomized
controlled trials (439 participants attended) were performed to evaluate
vagus nerve stimulation for partial seizures. The results were promising to
be an effective and well-tolerated treatment in these trials. Outcomes of the
overall efficacy analysis showed that vagus nerve stimulation, using the
high stimulation paradigm, was significantly better than low stimulation in
decreasing frequency of seizures. In addition to this positive feedback,
researchers suggested that vagus nerve stimulation was well-tolerated, and
withdrawals during the therapy were rare. Some adverse effects reported
included hoarseness, cough, dyspnea, discomfort, paresthesia, nausea and
headache.
In 2016, Englot et al. researched the effect of vagus nerve stimulation on
seizures. They examined 5554 patients from the vagus nerve stimulation
therapy Patient Outcome Registry. In addition, researchers performed a
systematic review of the literature containing 2869 patients through 78
studies. Registry data demonstrated a progressive amelioration over time in
seizure freedom after vagus nerve stimulation therapy. Meanwhile, >50% of
patients responded to vagus nerve stimulation therapy. Also systematic
literature review results were found to be parallel with the registry analysis
with minor differences.
Risks of the implanted device for vagus nerve stimulation are mostly
reported as pain where the incision is made to implant the device, infection,
struggle to swallow, or vocal cord paralysis. Vocal cord paralysis is usually
temporary, but it is an important risk when it would be permanent. It is
reasonable to believe that the complication frequency increases with a
longer follow-up time, considering the repeated surgeries needed due to
depleted batteries and hardware being worn out. The most common
complications are postoperative hematoma, infection, and vocal cord palsy.
These complications may cause major suffering and even be life
threatening. However, we understand from clinical studies’ evidence that
vagus nerve stimulation is safe for most people. Collectively, it should be
kept in mind that this therapy has some risks as other surgical methods, both
from the incision to implant the device and from the
unexpected/overstimulation of sensitive vital organs, such as the brain and
heart.
Surgery for implantation of vagus nerve stimulation can cause some
complications, but they are occasional and are similar to the dangers of
having other types of surgery. However, we want to emphasize some
specific side effects of vagus nerve stimulation. Some of the adverse/side
effects can be listed as:
 Voice fluctuations
Throatiness
Throat discomfort
Headaches
Cough
Dysregulation of respiratory system
Trouble swallowing
Itchiness of the skin
Insomnia
Worsening of sleep apnea
It is commonly documented that most people tolerate the side effects. These
side effects disappear or lessen over time, but some of them can persist for
as long as the patient uses the implanted device for vagus nerve stimulation.
Additionally, optimal adjusting of the electrical impulses can minimize
most of these effects. When side effects are intolerable, users should turn
off the device and consult his/her doctor immediately.
However, it is essential to consider the pros and cons of implanted vagus
nerve stimulation carefully before deciding to apply this method on one’s
body. Although implanted vagus nerve stimulation can be an effective
option for particular disorders, it would be safe/efficient to ask a doctor if
this therapy is appropriate. Before deciding on surgery, clinicians will do a
physical examination, some blood tests, and other tests to be sure about any
health concerns that might be a problem. Surgery to implant the vagus
nerve stimulation device can be done on an outpatient basis, though some
surgeons recommend staying overnight. The surgery usually takes less than
2 hours. In general, less than 3 incisions are made in the chest or in the
axillary region, and the other is on the left side of the neck.
Vagus nerve blocking therapy is similar to vagus nerve stimulation. In a six
month open-label trial involving three medical centers in Norway, Mexico,
and, Australia, vagus nerve blocking has helped 31 obese participants lose
an average of nearly 15% of their excessive weight.
Vagotomy is another optional therapy for peptic ulcer disease. Cutting the
vagal nerves, which are innervating acid secretion in the stomach, has been
asserted as an effective remedy for peptic ulcer. But when this method is
applied to patients, an unwanted decrease in stomach movement pattern
occurred. This side effect should be kept in mind and should be fixed for
optimum physiological stomach working. Additionally, vagotomy is
currently being investigated as a less invasive optional weight loss option to
gastric bypass surgery. The purpose of this method is limiting the feeling of
starvation8 .
We should emphasize that one serious side effect of vagotomy is cobalamin
(Vitamin B12 ) deficiency that can cause pernicious anemia. When the
stomach produces an abnormally reduced amount of acid, the balance of the
intrinsic factor down regulates, and consequently, vitamin deficiency
occurs. In other words, vagotomy decreases the acid in the stomach that
eventually leads to the deficiency of cobalamin. Untreated vitamin B12
deficiency can lead to nerve damage, tiredness, paranoia, depression,
anxiety, memory problems and dementia, nerve problems such as numbness
or tingling, weakness in muscles, and some gastrointestinal complaints,
such as constipation, gas, diarrhea and lack of appetite9 .
On the other hand, many people with chronic digestive concerns also have
low cobalamin levels, which is often due to not having adequate vagus
stimulation of the parietal cells in the gastrointestinal system. This situation
leads to low intrinsic factor. Intrinsic factor is the chemical that has a vital
role in the absorption of cobalamin in the stomach. Also, low acidity in the
stomach may cause sensitivity, allergic reactions, gut infections, and
inflammation10 .
Migraine Headache
Migraines can be defined as a recurring type of headache. Migraines cause
moderate to severe pain that is aching and pulsing. The pain often occurs on
one side of the head and may also have other symptoms, such as nausea,
vomiting, sensitivity to light and voice, and weakness. The American
Migraine Foundation guesses that more than 36 million Americans suffer
from migraines, and women are more vulnerable than men. Most people
start having migraine headaches between the ages of 10 and 40.
The efficacy, safety, and tolerability of noninvasive vagus nerve stimulation
for the acute treatment of migraine was evaluated by Tassorelli and his
colleagues in 2018. They performed a clinical study in different centers as
double-blind, randomized, and controlled. 248 participants with episodic
migraine with presence/absence of aura were randomized to receive
noninvasive vagus nerve stimulation within 20 minutes of ache onset. The
results of this study showed that noninvasive vagus nerve stimulation was
effective for pain freedom when compared with the control group.
Noninvasive vagus nerve stimulation demonstrated benefits across other
endpoints with pain relief at 120 minutes and was harmless and tolerable.
The researchers concluded that this trial supports the abortive efficacy of
noninvasive vagus nerve stimulation as early as 30 minutes and up to 60
minutes after migraine attack. Outcomes also propose effective pain relief,
tolerability, and practicality of noninvasive vagus nerve stimulation for the
acute treatment of episodic migraine. Finally, it can be concluded that the
role of noninvasive vagus nerve stimulation in migraine therapy requires
further clinical studies in large-scale, randomized, sham-controlled with
long-term follow-up11 .
Moreover, other groups of scientists evaluated the feasibility, safety, and
tolerability of noninvasive vagus nerve stimulation for the prevention of
chronic migraine attacks. In this context, multicenter and double-blind pilot
studies were performed to investigate noninvasive vagus nerve stimulation
in chronic migraine therapy. As the results of this study suggest,
noninvasive vagus nerve stimulation therapy was well-tolerated, and no
safety issues occurred during the trial. Study limitations included small
sample size, blinding challenges, and high discontinuation rate. According
to the authors, larger sham-controlled studies are needed. Although
researchers detected an amelioration in chronic migraine complaints in 15
participants, a bigger population is needed to confirm the effects of
noninvasive vagus nerve stimulation for chronic migraine headaches12 .
Furthermore, in a randomized, controlled, double-blind study, Straube and
others asserted that transcutaneous stimulation of the auricular branch of the
vagal nerve can be an option for the treatment of chronic migraine. After
one month of baseline, patients with chronic migraine were randomized to
receive 25 Hz or 1 Hz stimulation of the sensory vagal area at the left ear by
a handheld battery driven stimulator for 4 h/day through 3 months.
Participant complaints of headache days per 28 days were compared
between baseline and the last month of treatment. The Headache Impact
Test and the Migraine Disability Assessment questionnaires were used to
assess headache-related disability. 40 patients continued and completed the
study per protocol. 29.4 % of the patients in the 1 Hz group had a ≥50 %
reduction in headache days and 13.3 % in the 25 Hz group. The Headache
Impact Test and the Migraine Disability Assessment scores were
meaningfully better in both groups. Treatment-related serious adverse
effects were not reported. Treatment of chronic migraine by this therapy at
1 Hz was recorded as safe and effective. However, we should emphasize
that the findings must be confirmed with further clinical trials with a bigger
quantity of participants 13 .
The National Institute for Health and Care Excellence has issued guidelines
about transcutaneous stimulation of the cervical branch of the vagus nerve
for cluster headache and migraine. The guidelines state that “current
evidence on the safety of transcutaneous stimulation of the cervical branch
of the vagus nerve for cluster headache and migraine raises no major
concerns, whereas evidence on efficacy is restricted in quantity and
quality.” Thus, this method should only be used with special arrangements
for clinical authority, agreement, and review or research.
Relaxation techniques with vagus nerve
In light of the necessity to report the instructions and exercises in every
intervention study, control of the vagus nerve must be mentioned. Breathing
techniques for relaxation have already been used for more than centuries.
There is solid science behind deep breathing both to stimulate the vagus
nerve and to regulate our heart rate variability. It is now widely accepted
that deep breathing plays an important role in maintaining a healthy life
balance.
Considering the vagus nerve transmits signals from the circadian control
center in the brain can give us some clues about relaxation techniques with
the vagus nerve. Abnormal circadian rhythm affects the brain and then
alters normal melatonin and other hormone levels that can lead to problems
with the vagus nerve. Consequently, the rest of our body runs away.
Furthermore, the circadian control center in the brain sends messages to the
digestive system and lungs to produce mucin, the substance that keeps your
vital organs healthy and well-lubricated14 .
Collectively, we can conclude that optimum vagus nerve signalization
techniques, either physiological or with stimulation, play a role in
maintenance of a relaxed/healthy body, as well as get rid of stress and stress
related disorders15 .
The breathing techniques
The breathing techniques, including slowing down respiration cycles,
shifting to longer exhalations compared to inhalations, shifting the main
locus of respiration from the thorax to the abdomen, have been used for
many years in vagus nerve related relaxation.
On average, people take 10 to 14 breaths per minute. However, stimulating
the vagus nerve can be possible with approximately 5-6 breaths per minute.
Breathe in deeply, allow the stomach to expand, then breathe out very
slowly. Additionally, diaphragmatic breathing is known as natural
breathing. Especially slow and deep breathing with emphasis on long
exhalation is dominant across traditions. In the physically active mind-body
exercises, respiration can be synchronized with movement techniques. For
example, in some “tai chi chuan” styles, moving towards the body is
performed on inhale and moving outward on exhale.
Overall, some breathing methods may have a role on vagus nerve related
relaxation. One of them is:

Breathe in the fresh air and count one, two, three, four, and
five.
Hold the air in your lungs and count one, two, three, four, and
five.
Breathe out the polluted air/polluted things and count one,
two, three, four, and five
Wait for 5 seconds without inhalation or exhalation.
Repeat these steps 3 times.
As discussed, modulation of the respiratory system is related with our heart
as well as our nervous system. The vagus nerve connects all of this
signaling and releases neurotransmitters that can help us with relaxation16 .
Cold water
It is commonly known that the vagus nerve is stimulated when the body is
confronted with cold. Exposure to cold can lead to the down regulation of
the sympathetic system and up regulation of the parasympathetic system.
Taking into account the vagus nerve is under control of the parasympathetic
system, we can conclude that cold conditions lead to vagus nerve activation.
Splashing our face with cold water every morning and having a shower
with cold water are a routine lifestyle for many people. Also in the winter,
open a window in the morning for just a few seconds. Many people don’t
think about vagus nerve stimulation while doing these cold exposures. The
role of cold exposure in vagus nerve modulation can be researched more in
the future. Consequently, scientific evidence would support the cold
exposure effect via the vagus nerve 17 , 18 .
Singing, voice control, and tone
Can altering our tone of speech or voice affect the vagus nerve? When we
hear a certain type of music that evokes us, some emotions appear in our
brain. Also, we feel a good sensation in the chest when we hear and
appreciate the music rhythm. There is empirical evidence to suggest that
any stimuli that evokes positive emotion and arousal can evoke feelings of
admiration. Consecutively, those feelings are associated with engagement
of the vagus nerve.
Some experts offer that singing a song using the full capacity of the lungs
can be a good choice for relaxation. Investigation of relaxation with these
methods and the vagus nerve would be interesting. We already know the
muscles in the back of the throat activate the vagus nerve as they move, so
singing as loud as possible can have a role in vagus nerve stimulation.
Finally, another supportive idea for this hypothesis is oxytocin, the calming
hormone released when singing 19 .
Meanwhile, daily prayer, chanting, and meditation are the other methods for
vagus nerve modulation. It may feel silly or weird at first, but it works for
health and wellness, as what vibrates the throat stimulates the vagus nerve.
Most religions have some sort of chanting, singing, or meditation. Atheist
or just not down with religion? Try chanting whatever noise feels good for
you. We will discuss more in the next sections.
Finally, research shows that fasting can improve vagal tone as well. Fasting
may sound threatening, but it is easily accomplished by simply eating
dinner around 7pm and then not eating again until breakfast at 7 am. That
would be a 12 hour fast.
Key Points in one page
In a six month open-label trial involving three medical centers
in Norway, Mexico, and Australia, vagus nerve blocking
helped 31 obese participants to lose an average of nearly 15%
of their excessive weight.

248 participants with episodic migraine presence/absence with

aura attended a clinical study to receive noninvasive vagus
nerve stimulation within 20 minutes from ache onset.
Noninvasive vagus nerve stimulation was found effective to
get rid of pain.

Optimum vagus nerve techniques can be either physiological

or, with stimulation, play a role in maintenance of a healthy
body in addition to relieving stress and stress related disorders.

The vagus nerve stimulation is possible if we get 5-6 breaths

in per minute. Certain breathing methods may have a role on
vagus nerve related relaxation.

Cold exposure plays a role in vagus nerve modulation, but

scientific evidence is required to confirm this info.
Singing your favorite song using the full capacity of lungs can
be a good choice for relaxation.
 SECTION 12: CAN
MEDITATION
TECHNIQUES RELIEVE
OUR STRESS VIA VAGAL
ACTIVITY ?
Meditation
Meditation is an umbrella term for numerous ways to attain a relaxed state
of being. Many types of meditation have emerged as relaxation techniques
that have meditation components. All of them share the same goal of
achieving inner peace. Ways to meditate are guided meditation, mantra
meditation, mindfulness meditation, Qi gong, Tai chi, transcendental
meditation and yoga1 .
Various meditation techniques have been practiced by humans all over the
world for centuries. Practice of meditation was originally designed to help
understanding of the sacred and mystical forces of life. It can be defined as
a habitual process of training the mind to focus and redirect thoughts. Most
people participate in meditation for mind-body complementary medicine. It
can produce a deep state of relaxation and a restful mind. Therefore,
meditation is commonly used for relaxation and stress reduction.
During meditation, individuals focus attention and eliminate the stream of
jumbled thoughts that may be crowding their mind and causing stress. This
method may result in enhanced physical and emotional well-being. Sense of
calm, concord and steadiness are some results of meditation that can benefit
both emotional well-being and an overall healthy life. In addition to the
benefits of these results during a meditation session, people can also carry
and maintain well-being habits for a lifetime.
The emotional positive feedback of meditation can be listed as:

Achieve an optimal/better/less harmful viewpoint on stressful

situations
Gather new skills to manage stressful situations and habits
Enhancement of self-awareness
Concentrate on the present
No struggle for unnecessary things/circumstances
Decrease negative feelings
Improve thoughts and creativity
Increase tolerance and open-mindedness
Moreover, meditation might also be useful for various medical conditions,
especially if the root of the illness is caused by stress. Research suggests
that meditation has the potential for more than just temporal stress relief.
Although accumulated data of scientific research supports the health
benefits of meditation, some researchers believe it's not yet possible to
make conclusions about the possible benefits of meditation. Some clinical
studies suggest that meditation may help individuals to manage symptoms
of conditions such as anxiety, asthma, some cancer types, chronic pain,
major depression, cardiovascular events, hypertension, irritable bowel
syndrome, sleep disturbances and headaches2 , 3 .
Humans should be sure to talk to their health care provider about the pros
and cons of using meditation. It must be kept in mind that, when somebody
has health problems, meditation can worsen symptoms associated with
certain mental and physical health conditions. Furthermore, most clinicians
assert that meditation isn't a replacement for traditional medical treatment,
but it may be considered a useful additional treatment method.
Different types of meditation may comprise different methods. These may
vary depending on guidance or people’s decision. One of the most common
features in meditation is focused attention. Concentrating is generally
considered one of the most important elements of meditation that helps free
the mind from the many stressful and worrying situations. Mostly, attention
on such things as a specific object, an image, a mantra, or even breathing is
used for this method.
The other one is relaxed breathing. This practice involves deep, even-paced
breathing using the diaphragm muscle to expand the lungs. The purpose is
to breathe slowly, consequently taking in more oxygen. Also, reducing the
use of the shoulders, neck and upper chest muscles while breathing means
you breathe more efficiently.
A quiet setting is generally used by beginners. Practicing meditation may be
easier in a place that is as quiet as possible, including no television, radios
or cellphones. However, more skilled and experienced individuals may be
able to do it anywhere, especially in high-stress situations where they
benefit the most from meditation, such as a stressful work meeting or in
traffic4 .
Meditation can be formal or informal, however it suits your lifestyle and
situation. Some people perform meditation in their daily routine; they may
start and end each day with an hour of meditation. Some of the most
frequently used methods can be listed as:

Breathing deeply; this technique is suitable for beginners due

to the natural functioning of breathing and how it can be
adapted.

Focus all your attention on your breathing; think deeply on

feeling and listening, inhaling and exhaling through your
nostrils. When attention wanders, focusing on breathing would
help to recover attention.

Scanning body; when using this technique, focus attention on

some parts of the body. Thereby, awareness of the body's
various sensations (pain, tension, warmth or relaxation) would
enhance meditation.
Repeat a chant; everybody can create their own mantra,
whether it's religious or secular. Examples of religious mantras
include the Jesus Prayer in the Christian tradition, the holy
name of God in Judaism, or the “om” chant of Hinduism,
Buddhism and Eastern religions.

Walking and meditating; merging walking with meditation is

an efficient and healthy way to get relaxed. This technique can
be performed anywhere while walking, such as in a calm
forest, on a city sidewalk, or at the shopping mall. It is an
important point to slow down walking pace so that you’re
concentrating on your legs and feet, repeating action words in
your mind.

Engage in prayer; prayer is the most prominent and widely

practiced method of meditation. Vocalized and written prayers
can be found in most faith traditions.

Read and reflect; lots of people suppose they benefit from

reading poems or sacred texts and taking a few moments to
reflect quietly on their meaning. Although it seems weird, this
method is an effective meditation method.

Love and appreciation; in this type of meditation, focus

attention on a sacred image or being, weaving feelings of love,
compassion and gratitude into thoughts. Close your eyes and
use your imagination to see representations of the image,
which is the hallmark of this kind of meditation.
Throughout the centuries, many types of meditation techniques have
emerged to help people support mental awareness, physical well-being, and
get rid of stress. Finally, we can conclude that different kinds of meditation
methods are aiming to present humans a better life1 , 5 .
What is mindfulness meditation?
The term meditation refers to a wide-ranging set of practices that involve
training and regulating attention towards intentionally created mental
images, while perceiving or redirecting attention from distracting thoughts.
Meditation techniques involving sustained attention to a specific focus or
limited range of inner or outer experience have often been referred to as
concentrative or focused attention practices.
Mindfulness meditation inspires the practitioner to perceive wandering
thoughts that drift through the mind. Through mindfulness meditation, it
can be seen how thoughts and feelings tend to move in certain patterns.
Mindfulness meditation can help its practitioners to learn how to recognize
their minds and capacity.
Numerous studies assert that meditation, particularly mindfulness
meditation, is effective in lowering stress. Mindfulness meditation is the
most studied approach to meditation, with more than 2500 studies published
until this time. These studies suggest that meditation can improve life
energy, decrease stress, relieve anxiety, and reduce pain. Whenever the
vagus nerve receives the signals from mindfulness meditation techniques, it
sends a message to the brain that there is no risk to the body, and there is no
need to be in fight or flight. At that point, the brain sends the signals to the
autonomic nervous system to stimulate the parasympathetic nerves. As we
discussed, stimulation of the vagus nerve can affect several functions in
visceral organs and the whole body2 , 5 , 6 .
Relationship with vagus nerve and meditation
The vagus nerve plays an important role while people meditate. It is known
that the vagus nerve translates as “wandering nerve”. It roots from the brain
stem, then reaches down into the abdomen and connects with many major
organs participating in many of our bodily functions such as breathing,
digestion, heart rate, and other vital functions. So, meditation or any effect
on the vagus nerve can cause fundamental changes in the human body.
Essentially, the vagus nerve reverses the flow of information rather than
instructions flowing from your brain to your body. The nerve is instead
conveying the messages from the body back to the brain. By lowering
inhalation/exhalation rate, the vagus nerve notes that there is no reason to
breathe hard and fast, and consequently you should be able to relax. As the
vagus nerve travels around the body, it receives messages from visceral
organs, which humans do have conscious control over while meditating.
Actually, the main point of meditation can be suggested that we are in no
immediate danger and therefore have no cause to be stressed. The vagus
nerve is one of the main conveyors of relaxation messages to the brain. In
response to this message, the balance of the parasympathetic nervous
system and sympathetic nervous system changes to parasympathetic
regulation. Finally, as a result of parasympathetic weighing, our body would
start to relax, rest, and digest7 .
Meditation exercises can instruct attention to different parts of the body,
mostly to the skin and muscles, but also the viscera, to make up the body
awareness training factor. Initiation for awareness of the body is possible
with brain directions. On the other hand, the sensations are also governed
by the parasympathetic nervous system as well as the vagus nerve. Some
researchers even theorize that body awareness is central in the cultivation of
empathy8 .
Metacognition and cognitive improvement starts in the body, and
meditation exercises have a role in vagal tone. In conclusion, body
awareness could be involved in producing effects on emotional and
cognitive levels via voluntary and involuntary directions. Taking into
account the vagus nerve is one of the major components of the
parasympathetic (involuntary) nervous system, we can conclude that more
investigations would be necessary to enlighten on the role of vagal tone in
meditation.
Default mode network brain connectivity
Brain connectivity generally seems to increase by meditation practice
across multiple projections and associated social networks, as shown in
scientific studies. Luders et al. asserted that enhanced brain connectivity
can be possible with long-term meditation9 .
Meditation practices, especially mindfulness, are associated with better
connectivity between the executive, default mode network and projection
networks. Particularly, the default mode network is implicated in
neuroimaging studies among meditation practitioners. As it is known, the
default mode network is becoming dynamic when external stimulation and
work demand are low10 .
The role of the default mode network in cognitive skills can be seen as
opposing that of the executive network. In this situation, the default mode
network can be viewed as a task-negative network. Furthermore, the
functional connectivity between the default mode network and executive
networks process is complicated as vagal tone activity plays a role in these
processes. This mirrors what is constantly found in clinical studies applying
vagus nerve stimulation to individuals with treatment-resistant depression11 .
Major depression and anxiety disorder are associated with a disrupted
default mode network. Some clinical trials suggest hyperactivity and hyper-
connectivity among default mode networks, as well as hyper-connectivity
between default mode network and the limbic system , and decreased
connectivity between default mode network and executive network. Clinical
trials suppose chronic vagus nerve stimulation in patients with depression
displays a normalization of this etiology, gaining results similar to
meditation practice. Pardo et al. demonstrated that patients with major
depression, who are treatment resistant, responded to increased metabolism
in the default mode network12 .

The hallmarks of mindfulness meditation

Most people spend large parts of their lives on autopilot, unaware of what
they are experiencing, missing out on all the sights, sounds, smells,
connections, and appreciations. Some of that time, humans’ minds are
switched off, and other times, they are caught in thoughts from the past or
plans for the future; many of these thoughts are boring. Mindfulness
meditation can help us to be in the present and remind us to take control
over our reactions and repetitive thought patterns. Additionally, it can give
inspiration to pause, get a clearer picture of a situation, and respond more
proficiently.
Mindfulness meditation is a different state than our normal default way of
being. There are many different practices that help to support the
development of mindfulness, such as different types of sitting meditation,
movement, or even just being in nature.
Mindfulness involves the ability to observe any experience without getting
caught up in assigning a ruling to it. It is about educating an approach to
taking an active and curious interest in things precisely as they are, with no
efforts to alter or deny it. There is no anxiety of what may arise in
experienced situations or circumstances, nor is there agitated surprise by the
unexpected.
Additionally, there is a sense of fully noticing opinions, moods, feelings,
societies, and events. From side to side, this balanced observation comes
with an augmented awareness of temporariness, elaborations, and nuance.
There is no reason to reject things that are unpleasant, because the
judgments of good and bad are set aside in favor of open-minded, curious
observation .
When we are unable to receive all our qualities completely, it is quite hard
to observe them with nonjudgmental interest. This form of acceptance
comprises noticing unpleasant or difficult thoughts, feelings, and
sensations. In order to develop more mindfulness, we need to accept the
fact that pleasant states will not always be experienced during our lifetime.
Mindfulness also allows us to live/confront uncomfortable thoughts and
feelings with a greater sense of calm. A reduced amount of fear and
resistance are the main components of these methods. Similarly,
mindfulness involves taking an actively accepting stance of no pride, and
there is no shame as a result of an internal state.
Mindfulness time-outs are in the here and now. This pure awareness lives
only in the present moment with awareness of breath and the sensations in
the body. Rather than existing in a mental dream of the previous or
upcoming, mindfulness can give an opportunity to live intensely at this
moment. The difference between present moment mindful awareness and
being mentally or emotionally distant, indicates a real difference when
people are aware of it6 , 13 , 14 .
Key Points in one page
According to contradictive data reported by scientists about
the health benefits of meditation, some researchers believe it's
not yet possible to decide conclusions about the possible
benefits of meditation. But, during human centuries, many
types of meditation techniques have emerged to help people
support mental awareness, physical well-being, and get rid of
stress.

Due to more than 2500 studies published in scientific journals,

we can assert that mindfulness meditation is studied more than
other kinds of meditation.

Metacognition and cognitive improvement start in the body,

where meditation techniques can play a role in vagal tone.

The role of the default mode network in cognitive skills can be

seen as opposing that of the executive network. The landmark
discovery of the default mode network has led to an explosion
of interest in its role in attention and cognition. The default
mode network is associated with cognitive processes that
require internally-directed or self-generated thought, such as
mind-wandering, future thinking, perspective talking, and
mental simulation. The execution control network is engaged
during cognitive tasks that require externally-directed
attention, such as working memory, relational integration,
response inhibition, and task-set switching. Despite their
apparent cooperation, evidence from resting-state and task-
based research suggests that the default mode network and
executive control network tend to act in opposition. Activation
of one network typically corresponds to suppression of the
other. This antagonistic relationship is thought to reflect
opposing modes of attention, with executive control network
activity indicating focused external attention and default mode
network activity indicating spontaneous internal attention.
Mindfulness is also allowing oneself to live with or confront
uncomfortable thoughts and feelings with a greater sense of
calm.
 SECTION 13: MUSIC CAN
MODULATE OUR MOODS
Take advantage of the magical rhythm of music
Music is extensively listened to/performed for happiness, to reduce stress,
and to distract patients from unpleasant symptoms. Even though there are
wide variations in individual preferences, music seems to exert direct
physiologic effects through the autonomic nervous system. Several
scientific studies have reported that music effectively can relieve anxiety
and improve mental health. Music also improves the quality of life for
patients who receive palliative care (patients unfortunately at the last stage
of any disease), giving them a sense of comfort and relaxation.
Music is an indispensable part of human life all over the world. In recent
years, music therapy has been regarded as an expressive cure for various
disorders. Professional health experts use music and its physical, emotional,
intellectual, social, and mystical effects to help patients improve and
maintain their health. The cognitive function, emotional improvement,
social skills, and life energy of the patients are clinically proven to be
improved through music therapy1 .
Music can be performed as free improvisation, singing, song writing,
listening to the music, and discussing music. All music related
performances are believed to achieve treatment aims and objectives. The
efficacy of music treatment is evidence based and is considered both art and
science. Music therapy is widely performed in schools, medical hospitals,
cancer centers, and drug/alcohol addiction recovery programs.
One of the featured advantages of music therapy is the ability of all age
groups to listen/make music everywhere. Music therapy can benefit
children by improving communication, attention, inspiration, and
behavioral problems. The therapist either plays an instrument or listens to a
musical performance to keep everything grounded and in rhythm2,3 .
Different positive outcomes of music may be based on listener
characteristics, age, culture, medical conditions that affect hearing, musical
capacity, and understanding. Additional factors affecting music impact
include elements of the music, such as tempo, pitch, harmony, melody,
rhythm. Music and musical therapy may help patients physiologically and
emotionally. With regard to direct physiologic effects, even in animals,
music changes neuronal activity with entrainment processes that is,
synchronization or frequency coupling and tendencies towards temporal
periodic activity have been described as fundamental functional
characteristics, to musical rhythms in the lateral temporal lobe and in
cortical area of the brain. Entrainment to music is an extremely common
behavior, shared by humans of all cultures. It is a highly complex activity
which involves auditory, and also visual, proprioceptive and vestibular
perception. It also requires attention, motor synchronization, performance
and coordination within and across individuals. Hence, a large network of
brain structures is involved during entrainment to music. There are
relatively recent and growing types of mechanisms for neural entrainment
to music, as it may constitute a unique gateway to understanding human
brain function. For example, stable rhythms entrain respiratory patterns;
listening to classical music increases heart rate variability, a measure of
cardiac autonomic balance; however, listening to rock music decreases
heart rate variability (reflecting greater stress)4,5 .
Which kind of music is effective on the vagus
nerve?
Current research clarifies that stress through the tone of the autonomic
nervous system results from physical, environmental, or other psychosocial
stressors, where both the sympathetic and parasympathetic nervous systems
are involved in the regulation of functions including heart rhythms,
respiration, and blood pressure. Music performance is an appropriate
domain for studying an autonomic nervous system response to stressors.
Taking into account that vagal tone is a main component under autonomic
nerves, it can be thought that musical performance or listening to music can
play a role in vagus nerve stimulation.
There are wide individual and traditional variations in types of music
favored. Some kinds of music seem to have consistent physiological and
emotional effects on the human body. Impact of different kinds of music
vary in pressure, mood, and mental clarity. Scientists from the USA
researched the effect of grunge rock, classical, New Age, and designer
music on 144 persons. They found that grunge rock music significantly
increases hostility, sadness, tension, and fatigue; additionally significant
decreases were observed in caring, relaxation, mental clarity, and vigor. In
contrast, after listening to designer music (music designed to improve the
listeners’ mental health and boost immunity through the effect on the
autonomic system), significant escalations in caring, relaxation, mental
clarity, and vigor were measured, whereas significant reductions were found
in hostility, fatigue, sadness, and tension. The consequences for New Age
and classical music were found to vary. However, designer music was most
effective in increasing positive feelings and decreasing negative feelings.
Findings of these trials suggest that designer music may be beneficial in the
treatment of tension, mental disruption, and negative attitudes6 .
The involvement of the autonomic nervous system in health and illness and
the ability of music to affect the autonomic nervous system activity is
widely known. On the other hand, only a few studies have systematically
explored the therapeutic effects of music on the autonomic nervous system
as well as the vagus nerve. After a review of the experimental and
therapeutic literature exploring music and the parasympathetic nervous
system, neurovisceral integration perspective on the interaction between the
central and autonomic nervous systems is introduced. The construct of heart
rate variability is conferred both as an example of this complex interplay
and as a useful metric for exploring the sometimes understated effect of
music on autonomic response. Maybe near future investigations using
musical interventions will accumulate .
Therapy with Music has been used in geriatric nursing hospitals, but there
has been no extensive research into whether it actually has beneficial effects
on elderly patients with chronic diseases, such as cerebrovascular and
cardiovascular disease and dementia. In 2009, clinicians from Japan
investigated the effects of music therapy on the autonomic nervous system
and some biochemical markers. Plasma cytokine and catecholamine levels
in elderly patients were investigated to understand any protective effect of
music on particular chronic disorders. Researchers concluded that music
therapy enhanced parasympathetic activities and decreased congestive heart
failure, in addition to reducing plasma cytokine and catecholamine levels.
These results are valuable for investigation of music effect on advanced
future clinical trials, including the effect of vagal tone.
The importance of relaxation via music
As we discussed, the vagus nerve plays a role in the whole body’s
relaxation via surgical and non-surgical methods. Also it should be
considered that some sounds can affect vagal activity. Sound healing
therapies use music to improve physical and emotional health as well.
Sound healing based methods include:

Listening to music
Singing along loudly to music or a melody
Moving to the beat of the music
Meditating with sound such as “om”
Playing a musical instrument
Curing with sound has been believed to date back to ancient centuries.
Interestingly, without being based on scientific evidence, our grandparents
used music to cure various mental disorders. Throughout history, music has
been used to boost morale in military crowds, help people work faster and
more productively, and even protect against evil spirits by chanting. More
recently, researchers have linked music to a quantity of health benefits,
from boosting immune function and lowering stress levels to improving the
health of newborn babies7 .
Musical performance based therapy can decrease stress and endorse
relaxation. Canadian scientists have shown that music is more effective than
prescription drugs in reducing anxiety levels before operation. Another
clinical study demonstrated a 30-minute music therapy session combined
with traditional care after spinal surgery reduced pain. Additionally, music
therapy is administered by creating, listening, singing, or performing to
music. We can understand from recent trials that music can be used for
physical rehabilitation, pain control, and some neuropsychiatric disorders8 .
Key Points in one page
It is proven with scientific studies that music therapy can
benefit humans in improved communication, attention,
inspiration, and some behavioral problems.

Performing music is an appropriate thing for responding to

stressors via the autonomic nervous system and vagus nerve as
well.
A 30-minute music therapy session was found successful to
reduce pain. It was documented in clinical studies that music
plays a role in physical rehabilitation, pain control, and some
neuropsychiatric disorders.
 SECTION 14: THE
REMEDIES FOR HEALING
DAMAGED VAGUS NERVE
Damaged vagus nerve
When the vagus nerve is abnormally up/down regulated, the brain’s
hypothalamus cannot transport signals to the brain’s pituitary gland
properly. Similarly, imbalanced signalization may lead to confused adrenal
gland functioning. This system is identified as the HPA axis, and if this
transport axis is affected, several hormones, such as cortisol, CRH, ACTH,
and oxytocin, can get over/under produced. These hormonal fluctuations
may cause a combination of fatigue, lack of motivation, anxiety, insomnia,
and other stress related disorders.
People can experience a vasovagal response due to a stressor or
overstimulation of the vagus nerve at some point. Blood pressure lowers,
heart rate slows, and the blood vessels in your legs widen, which can cause
nausea or fainting. This is a generally harmless response that goes away on
its own; however, some people who experience it more chronically may
need to seek medical help.
Various problems linked with vagus nerve dysfunction include: obesity,
anxiety, mood disorders, bradycardia, gastrointestinal diseases, chronic
inflammation, fainting, and seizures. Of course, most of these conditions
outlined can lead to further illness; for example, obesity and inflammation
are both linked with cancers and diabetes. Anxiety or mood disorders might
also lead to depression.
The vagus nerve plays a vital role in the complex processes of our digestive
tract, including signaling the muscles in the stomach to contract and push
food into the small intestine. When the vagus nerve is damaged, it can't
transport the signals normally to our visceral organs. As a result of these
communication problems, some organs’ innervation are disrupted or don’t
work properly for healthy body maintenance. Although signalization of the
visceral organs-brain does not completely depend on the vagus nerve, we
can confront some major complications because of vagus nerve damage.
The principle sensory nerve to the visceral organs, including the heart and
reticuloendothelial system, is the vagus nerve. It is a paired structure,
arising in the brain stem that descends through the thorax and abdomen to
innervate the visceral organs. Damage to the nerve that helps your organs
and organ systems to function can cause a condition called autonomic
neuropathy. This nerve damage disturbs signal processing between the
autonomic nerve system and the brain. Injured autonomic nerves can affect
your: blood pressure, heart rate, perspiration patterns, bowel movements,
bladder emptying, and digestion.
The vagus nerve can be damaged by diseases. Uncontrolled high blood
sugar level can deteriorate the nerves. Diabetic neuropathy is one of the
common complications of diabetes.
Cardiac alterations initially start with a relative increase of the sympathetic
tone, since diabetic neuropathy first affects the longest fibers, such as those
of the parasympathetic system (like the vagus nerve). Sympathetic
denervation begins at the following stage by affecting the heart from the
apex toward the base, gradually impairing ventricle function and resulting
in cardiomyopathy.1
It should be taken into account that the relationship between malign-
autoimmunity disease and type1 Diabetes mellitus has been reported
recently. Recent studies have reported autoimmunity is a causative factor in
progression of diabetic autonomic neuropathy. Collectively, we can think
that type1 diabetes may worsen the neuropathy via both malign-
autoimmunity and higher sugar levels. In conclusion, people with diabetes,
especially type1, would be affected negatively because of dysregulated
vagus nerve function2-4 .
Risk factors for the vagus nerve
Sometimes, the vagus nerve overplays to certain stress triggers, such as
exposure to extreme heat, fear of bodily harm, the sight of blood or having
blood drawn, or straining, including trying to have a bowel movement or
standing for a long time.
As discussed in section 7, which cause the heart rate to slow. When it is
over regulated, a sudden drop in heart rate and blood pressure may happen.
This unexpected situation is also known as vasovagal syncope.
The vagus nerve and other nerves in our body can be affected by certain
diseases and conditions. Thus, our nerves can be sometimes disordered
seriously and lose function temporarily or permanently. Diseases and other
unwanted conditions play a role in nerve damage upon blood circulation,
directly. We listed the diseases and other factors that play a role in nerve
damage, as well as the vagus nerve:

Type I Diabetes mellitus

Type II Diabetes mellitus
Surgery on abdominal or esophageal area
Various Infections
Particular medications that have an effect on gastrointestinal
movement
Scleroderma disease
Central nervous system disorders
Parkinson's disease
Multiple sclerosis
Hypothyroidism
Indication of vagus nerve dysfunction
How can we understand whether our vagus nerve is functioning optimally?
The answer is under the clinician’s medical examination. To test the vagus
nerve, a doctor can check the gag reflex. During this kind of examination,
the doctor may use a soft cotton pad to titillate the back of the throat on
both sides. This should cause the person to gag. If somebody doesn’t
respond to this examination, we may think something is wrong with the
vagus nerve.
A damaged vagus nerve may cause a condition called gastroparesis. This
syndrome affects the involuntary contractions of the digestive system,
which prevents the stomach from properly emptying5 . Symptoms of
gastroparesis can be listed as:

Nausea and vomiting

Acid reflux
Loss of appetite or feeling full even at the beginning of the
meal
Abdominal discomfort or swelling
Mysterious weight loss
Alterations in blood sugar
Some people can confront gastroparesis after undergoing a Vagotomy
method, which removes all or part of the vagus nerve6 .
Which symptoms give a clue about a damaged
vagus nerve?
Clinicians have shown vagus nerve damage can have a range of symptoms,
since the nerve is covering an extensive area in our body and affects various
areas where it is not touched directly7 . Potential symptoms of a damaged
vagus nerve can be listed as:

Struggle to speak
Partial voice loss
Hoarse or chesty voice
Difficulty drinking liquids
Injury in the gag reflex
Ear pain
Infrequent heart rate
Atypical blood pressure
Reduced stomach acid
Nausea and vomiting
Abdominal inflating and pain
For most people, it can be said that side effects are tolerable. The conditions
listed above may lessen over time; nevertheless, particular side effects may
remain. An implanted device or other methods for vagus nerve stimulation
can be an optional remedy for remaining side effects. The methods are
varying; one such method is adjusting the electrical impulses to help
minimize side/adverse effects. However, it should be kept in mind that
devices/other methods can be intolerable for some individuals. The solution
in this situation is to shut it off temporarily or permanently.
How can we treat the damaged vagus nerve?
The vagal nerve is the 10th cranial nerve and is composed of approximately
80% afferent sensory nerve fibers that transfer messages from the body to
the central nervous system. The vagus nerve comprises 3 different types of
fibers according to their conduction velocity. The vagal A-fibers and the
vagal B-fibers are myelinated and have a high conduction velocity. The
vagal C-fibers are small and unmyelinated and require higher currents to be
activated. Treatment of these myelinated and unmyelinated nerves are
complicated and difficult due to their structural composition.
Pharmacological remedies
The afferent fibers of the vagal nerve have cell bodies in the nodosal and
the jugular ganglion. The afferent fibers form synapses in different nuclei of
the brainstem, the spinal nucleus of the trigeminal nerve, the nucleus of the
solitary tract, the nucleus ambiguous, and the dorsal motor nucleus of the
vagal nerve. All of these connections are made by neurotransmitters in our
body. When considering the mechanisms that play a role in neurotransmitter
regulation, drugs may have a role in vagus nerve stimulation or inhibition.
Today, there is no pharmacological treatment approach for vagus nerve
modulation. However, researchers may discover medication/medications
soon. These candidate drugs may be effective on neurotransmitter
modulation.
Key Points in one page
Numerous problems are linked with vagus nerve dysfunction:
obesity, anxiety, mood disorders, bradycardia, gastrointestinal
diseases, chronic inflammation, fainting and seizures.

As the other nerves, the vagus nerve also can be affected by

certain diseases and conditions, temporarily or permanently.
Diabetes mellitus, infections, scleroderma disease, central
nervous system disorders, and Parkinson's disease are the
factors that play a role in vagus nerve damage.

A damaged vagus nerve may cause a condition named

gastroparesis.

Struggle to speak, partial voice loss, hoarse or chesty voice,

difficulty drinking liquids, injury in the gag reflex, and
abnormal heart rate are the symptoms of an impaired vagus
nerve.

The vagal C-fibers are small and unmyelinated and require

higher currents to be activated.
Pharmacological treatment approach for vagus nerve
modulation is still under investigation.
 SECTION 15:
IMPLANTABLE AND NON-
IMPLANTABLE DEVICES
FOR VAGUS NERVE
STIMULATIO N
Implantable Vagus nerve stimulators
The action of the implantable vagus nerve stimulation device is similar to a
cardiac pacemaker. The implantable method includes a generator device
surgically placed under the skin in the left chest area, usually below the
collarbone. The vagus nerve stimulation electrode is tunneled under the skin
to the neck, where it is located in the left cervical vagus nerve.
An external programmer is used to control the stimulation parameters of the
device to deliver pre-programmed intermittent electrical pulses to the vagus
nerve. Moreover, a patient with epilepsy can activate the system when
sensing the onset of a seizure to deliver an additional dose of stimulation by
passing a magnet over the area of the chest where the device is implanted.
The device is powered by a lithium battery that must be controlled every
few years1-3 .
As we discussed in section 8, reports of adverse effects of implantable
vagus nerve stimulation therapy can be listed as voice alteration, headache,
neck pain, cough, and obstructive or central sleep apnea, sleep breathing
disorders. In 2017, Giordano and colleagues reported on surgical techniques
for vagus nerve stimulation implantation and related acute and delayed
morbidity. Late complications of vagus nerve stimulation therapy related to
the device and to stimulation of the vagus nerve include, but are not limited
to, delayed arrhythmias, hoarseness, dyspnea, coughing, obstructive sleep
apnea, stimulation of the phrenic nerve, and tonsillar pain mimicking
glossopharyngeal neuralgia4 .
In another clinical trial, 23 participants were evaluated with medically
refractory epilepsy who underwent sleep testing previously and
subsequently vagus nerve stimulation implantation. 18 patients underwent
endoscopic laryngeal examination post-vagus nerve stimulation
implantation. Also, statistical analysis was carried out to assess an
association between laryngeal motility alterations and sleep breathing
disorders. They showed that vagus nerve stimulation implantation caused a
new-onset of mild/moderate sleep breathing disorders in 11 individuals. In
conclusion, it was suggested in this trial that there is an association between
vagus nerve stimulation and sleep breathing disorders, which should be
investigated on patients before and after vagus nerve stimulation
implantation in further studies5 .
In 1997, the FDA approved a vagus nerve stimulation device called the
NeuroCybernetic Prosthesis (NCP®) system (Cyberonics, Houston, TX)
through the Premarket Approval process. The device was approved for use
as an adjunctive treatment of adults and teenagers older than 12 years with
medically refractory partial onset seizures. Subsequently, the Cyberonics
received premarket approval authorization by the FDA for vagus nerve
stimulation Therapy™ in July 2005. The device has been used for the
adjunctive long-term treatment of chronic or recurrent depression for
patients (older than 18 years) who are experiencing a major depressive
disorder and have not had an adequate response to four or more
antidepressant medications6 .
In 2017, Cyberonics ultimately received premarket approval from the FDA
expanding the indicated use as adjunctive therapy for seizures in patients
who are older than 4 years and with partial-onset seizures that are resistant
to antiepileptic medications.
Non-implantable vagus nerve stimulation devices
Non-implantable or transcutaneous vagus nerve stimulation is being
considered as a noninvasive alternative to surgery for vagus nerve
stimulation. Approaches of transcutaneous vagus nerve stimulation are used
for transcutaneous stimulation of the cervical branch of the vagus at the
neck. Also, the auricular branch of the vagus nerve at the concha of the
outer ear has been investigated by scientists.
A non-invasive vagus nerve stimulation device called the gammaCore®
(ElectroCore, LLC, NJ) is currently being investigated for the treatment of
various types of primary headaches, including migraine and cluster
headaches, and for the treatment of sporadic, chronic, and menstrual
migraines.
Several patients with persistent headache do not effectively respond to
medication therapies. New non-invasive, non-pharmacologic approaches
are needed to treat the pain associated with these headache types. The
gammaCore® non-invasive vagus nerve stimulator is proposed to be an
optional therapy for these patients.
The device contains a portable stimulator with a battery, signal generating
electronics, and digital control user interface that controls signal amplitude.
Moreover, the device is being investigated as a non-invasive alternative to
implantable vagus nerve stimulation for indications such as pain, epilepsy,
tinnitus, and depression. The gammaCore® is released in the USA and
European Union for acute treatment of pain associated with episodic cluster
headache in adult patients.
Difference of external vagus nerve stimulation
devices and traditional clinical devices
The main difference between traditional devices and external vagus nerve
stimulators is application techniques. External non-invasive devices are not
implanted right on the nerve, like clinical devices. External vagus nerve
stimulation devices produce electrical signals that can pass through the skin
and muscle of the neck. Invasive traditional vagus nerve stimulation devices
avoid exciting smaller fibers in the vagus nerve that convey pain.
Conversely, larger fibers going into the brain are more likely the targeted
site for potential treatments. It seems difficult to target these fibers by
external device to stimulate specific nerve fibers.
How should vagus nerve stimulation devices be
used, and what are the potential risks?
First, it must be taken into account that invasive vagus nerve stimulation
therapy requires a surgical operation. Generally, two small incisions are
made by a surgeon: one on the left lower side of the neck and a second
along the left side of the chest. The vagus nerve stimulation device is
implanted in the chest wall, located between the Carotid artery and the
jugular vein. When commercial vagus nerve stimulation devices are not
implanted adequately and not used with control of the clinician, the
impulses may have serious potential side effects like cardiac arrest. because
the vagus nerve also covers the heart and other vital visceral organs,
clinicians should consider the potential risk of the device. For that reason,
vagus nerve stimulation devices are usually administered to the right side of
the nerve, because it has less direct connection to the heart.
The vagus nerve plays vital roles in the body that should be protected.
Inopportunely, long-term side effects of vagus nerve stimulation devices are
not known completely. In older people, these nerves are more vulnerable to
damage. While treating symptoms at the central nervous system, we should
keep in mind the potential harm to the peripheral nervous system. Like
many medical interventions, it’s a balance between the treatment’s benefits
and discomfort and whether the latter can be tolerated7 .
Overstimulation of nerves can release neurotransmitters that cause
inflammation, imbalanced bowel movements, some psychological changes,
and cardiovascular events. Likewise, the arrangement of vagus nerve
stimulation is critical not to damage any organs. People should keep in
touch with a clinician who specializes in the vagus nerve stimulation area.
The vagus nerve stimulation devices, especially invasive ones, should only
be available through a prescription. A clinician who is accustomed with the
clinical trials and technology will have the correct expertise. The non-
invasive devices are relatively new, but when used in a clinical setting, they
could reduce patient risk of potential complications due to surgical
implantation of the device8 .
Treatment of other conditions with vagus nerve
stimulation
Dawson et al. showed in a small randomized pilot study that implantable
vagus nerve stimulation can be effective for patients with upper limb
dysfunction after ischemic stroke. They concluded that vagus nerve
stimulation paired with rehabilitation was acceptably safe and feasible in
participants with upper limb motor deficit after chronic ischemic stroke.
Limitations of this study include a small sample size, lack of blinding to
either the physiotherapist delivering the therapy or the subject, and no
control group 9 .
Kreuzer et al. reported the results of a single-arm pilot study of
transcutaneous vagus nerve stimulation with two different devices
(CerboMed CM02 and NEMOS) for the healing of tinnitus. The scientist
researched the feasibility of transcutaneous vagus nerve stimulation over a
period of 6 months and concluded there was no clinically relevant
improvement of tinnitus complaints. Additionally, they suggest
transcutaneous vagus nerve stimulation to be considered safe in patients
without a history of cardiac disease10 .
Huang et al. documented the results of a pilot randomized controlled trial of
a transcutaneous vagus nerve stimulation device (TENS-200) for the
treatment of decreased glucose tolerance. The treatment period was 12
weeks in duration. Comparisons were made between treatment and control
groups for the total body weight, body mass index, and measures of systolic
blood pressure. Additionally, they collected the values of fasting plasma
glucose, 2-hour plasma glucose, or glycosylated hemoglobin (HbAlc). The
results are hopeful for advanced research. Two-hour glucose tolerance was
reduced with therapy. Furthermore, transcutaneous vagus nerve stimulation
significantly decreased systolic blood pressure over time compared with the
control group. Finally, the authors concluded that transcutaneous vagus
nerve stimulation is a promising, simple, and cost-effective treatment for
impaired glucose tolerance and pre-diabetes with minor risk of side-effects11
.
Huang et al. also researched the sympathetic-vagal balance against
endotoxemia. The goal of the current study was to establish a convenient
and effective approach to anti-inflammation treatment by rebalancing the
sympathetic vagal system via vagal nerve stimulation. After they evaluated
various parameters that are related with endotoxemia, they concluded that
sympathetic and vagal nervous systems are evoked by endotoxemia. The
over stimulation of the sympathetic system leads to sympathetic-vagal
disequilibrium. The rebalance of the sympathetic and vagal system is
crucial for patients in a critical situation12 .
Hasan et al. reported a randomized, sham-controlled, double-blind pilot
study of the safety and efficacy of transcutaneous vagus nerve stimulation
(CM02 device, CerboMed GmbH, Erlangen, Germany) in 20 individuals
with stable schizophrenia. The primary results were evaluated with the
Positive and Negative Symptom Scale total score between the baseline and
12th week. Although an ameliorative effect was detected with vagus nerve
stimulation, this healing effect was not statistically significant. The
treatment was well-tolerated with no significant adverse effects associated
with use of the vagus nerve stimulation device. The authors concluded that
neither psychopathological and neurocognitive measures nor safety
measures showed significant differences between study groups. On the
other hand, further study of overall patterns of symptom alterations with the
use of a vagus nerve stimulation device may be warranted in the treatment
of individuals with schizophrenia13 .
Kostov et al. researched the long-term effects of vagus nerve stimulation on
seizure frequency in 30 patients with Lennox–Gastaut syndrome. In this
study, parameters investigated the total number of seizures and different
seizure types. The average decrease in the number of seizures was detected
as 60.6%. The effects of vagus nerve stimulation changed considerably
between seizure types. The most positive effects were observed with atonic
seizures (80.8% median reduction, number of responders: 8/12), whereas
the least effects were with generalized tonic-clonic seizures (median
reduction 57.4%, number of responders: 11/20). Additionally, the authors
reported adverse effects; increased salivation and voice alteration were
frequently seen in participants who received the therapy14 .
The www.clinicaltrials.gov database identified studies in various phases
investigating the effects of implantable vagus nerve stimulation on
conditions including, but not limited to, cluster headaches, active Crohn’s
disease despite treatment with a tumor necrosis factor antagonist drug,
myocardial function in heart failure, enteroendocrine secretion and glucose
metabolism in Type 2 diabetes-related obesity, rheumatoid arthritis, and
recovery from minimally conscious or persistently vegetative states after
traumatic brain injury15 . In December 2019, the FDA had not approved the
use of any type of implantable vagus nerve stimulation device for these
indications. Well-designed, randomized clinical trials with larger sample
populations are needed to demonstrate the safety and efficacy of
implantable vagus nerve stimulation therapy as a treatment for any of these
conditions.
Key Points in one page
An implantable vagus nerve stimulation device works like a
cardiac pacemaker. Side/adverse effects of implantable vagus
nerve stimulation therapy can be voice change, headache, neck
pain, cough, and obstructive or central sleep apnea.

A non-invasive vagus nerve stimulation device is currently

being investigated for the treatment of various types of
primary headaches, including migraine and cluster headaches,
and for the treatment of sporadic, chronic, and menstrual
migraines.

Although non-invasive vagus nerve stimulator devices have

some advantages, it seems difficult to target specific fibers by
an external device.

The vagus nerve stimulation devices, especially invasive ones,

should only be available through a prescription.
The www.clinicaltrials.gov database identified studies in
various phases investigating the effects of vagus nerve
stimulation on conditions including, but not limited to, cluster
headaches, active Crohn’s disease despite treatment with a
tumor necrosis factor antagonist drug, myocardial function in
heart failure, enteroendocrine secretion and glucose
metabolism in Type 2 diabetes-related obesity, rheumatoid
arthritis, and recovery from minimally conscious or
persistently vegetative states after traumatic brain injury.
 SECTION 16: A BIG
HEARTFELT THANKS,
DEAR FRIENDS.
A Sweet Friendship Refreshes The Soul.
Buddh a

A big heartfelt thanks!

Thank you for choosing How vagus nerve therapy can improve your life:
The new medical revelations for building self confidence, avoiding anxiety,
and reducing depression and reading it. We sincerely hope the information
here has been helpful to improve whatever feeling or situation that led you
here seeking help.
We hope this book was an easy and enjoyable read and was able to help you
understand how listening to your body and paying attention to the vagus
nerve will significantly improve your quality of life.
The next step is applying everything you learn here and starting your
healing journey. Remember, it’s never too late, and you’re not alone.
I would also like to remind you that for those who bought the book there is
an exclusive gift of my in-depth course on the topics mentioned in the book.
In particular I will explain:
The secrets of the great Yogis and how they reached such a
high level in a short time.
A simple trick to live better and longer (small spoiler: it has to
do with breathing).
A method to achieve all the goals you want and quit
procrastinating (lose weight, do more sports, finish school,
 start a business ... does that mean anything to you?)
And much more

Here is the link to the course

Https://Emma.wisementorpress.com/Course 1

You can help not only yourself but others too. Recommend this book and
course and share what you have learned about the amazing healing power
of the vagus nerve. Many will appreciate it. The power of changing many
lives is in your hands now!
If you liked this book and want to discover similar topics, feel free to write
a message with your name to this email:

Emma@wisementorpress.com

and you will receive a preview of my future books for FREE

Reviews and feedback
Amazon reviews are very helpful and important to any author. If you enjoy
this book, it would be much appreciated if you could take a moment of your
time to share your positive opinions and post a review. It doesn’t have to be
very long. Just a rating and a few words are enough to leave a lasting
impression on future readers, who could also gain many benefits from the
knowledge shared here. Here is the link if you will have the pleasure to
leave us your thoughts on the book. We look forward to hearing from you!

Https://Amzn.to/3iUGUYC

For any general feedback about the book, please feel free to contact us at
this email:

Contact@wisementorpress.com

We love hearing from our readers!

 GLOSSARY
Abdomen
The part of the body between the thorax and pelvis in humans and in other
vertebrates.
Acupuncture
A form of alternative medicine and a key component of traditional Chinese
remedy in which thin needles are inserted into the body.
Alzheimer’s disease
An irreversible, progressive brain disorder that gradually deteriorates
memory and thinking skills and, eventually, the ability to carry out the
simplest tasks.
Amygdala
Also named corpus amygdaloideum, it is an almond-shaped set of neurons
located deep in the brain's medial temporal lobe. It plays a key role in the
processing of emotions; the amygdala forms part of the limbic system.
Anaerobes
An anaerobic organism or an anaerobe is any organism that does not require
oxygen for growth.
Anxiety
A feeling of worry, nervousness, or unease characteristically about an
imminent event or something with an uncertain outcome.
Anxiolytic
A medication or other intervention that inhibits or relieves the mood of
anxiety.
Atrial fibrillation
Irregular and rapid heart rate that can increase the risk of strokes, heart
failure, and other heart-related complications.
Autonomic nervous system
The part of the nervous system of vertebrates that controls involuntary
actions of the smooth muscles, heart, and glands.
Baroreflex
The reflex mechanism by which baroreceptors regulate blood pressure that
includes transmission of nerve impulses from the baroreceptors to the
medulla in response to a change in blood pressure and that produces
vasodilation and a decrease in heart rate when the blood pressure increases
and vasoconstriction and an increase in heart rate when blood pressure
decreases.
Bipolar disorder
Also known as manic depression, a mental health condition that causes
extreme mood swings including emotional highs (mania or hypomania) and
lows (depression).
Brain cortex
The thin layer of the brain that covers the outer portion of the cerebrum and
plays a key role in attention, perception, awareness, thought, memory,
verbal activity, and consciousness.
Brainstem
The stem-like part of the base of the brain that is connected to the spinal
cord and controls the flow of messages between the brain and the rest of the
body, also controls basic body functions such as breathing, swallowing,
heart rate, blood pressure, consciousness, and whether one is awake or
sleepy.
Carotid artery
Major blood vessels in the neck that supply blood to the brain, neck, and
face.
Carotid sheath
An anatomical term for the fibrous connective tissue that backgrounds the
vascular compartment of the neck, it is part of the deep cervical fascia of
the neck below the superficial cervical fascia, meaning the subcutaneous
adipose tissue immediately beneath the skin.
Cholecystokinin
A hormone which is secreted by cells in the duodenum and stimulates the
release of bile into the intestine and the secretion of enzymes by the
pancreas.
Cortisol
A steroid hormone that controls a wide range of processes throughout the
body, including metabolism and the immune response.
Cranial nerves
Emerges directly from the brain, in contrast to spinal nerves. Ten of the
cranial nerves originate in the brainstem.
Diaphragm
Thin skeletal muscle that sits at the base of the chest and separates the
abdomen from the chest and contracts when we inhale.
Dorsal motor nucleus
The vagus nerve (or posterior motor nucleus of vagus) is a cranial nerve
nucleus for the vagus nerve in the medulla that lies ventral to the floor of
the fourth ventricle.
ECT
Electroconvulsive therapy that is a medical treatment most commonly used
in patients with severe major depression or bipolar disorder that has not
responded to other treatments.
Encephalopathy
A disease in which the functioning of the brain is affected by some agent or
condition (such as viral infection or toxins in the blood).
Epigenetic
Epigenetic is the study of heritable phenotype changes that do not involve
alterations in the DNA sequence.
Epilepsy
Neurological disorder marked by sudden recurrent episodes of sensory
disturbance, loss of consciousness, or convulsions, commonly related with
abnormal electrical activity in the brain.
Esophagus
A muscular tube connecting the pharynx with the stomach.
FDA
The Food and Drug Administration is a federal agency of the United States
Department of Health and Human Services.
GABA
Gamma-aminobutyric acid, or γ-aminobutyric acid, is the chief inhibitory
neurotransmitter in the developmentally mature mammalian central nervous
system. Its principal role is reducing neuronal excitability throughout the
nervous system.
Gastro-intestinal motility
The contraction of the muscles that mix and propel contents in the
gastrointestinal tract.
Glutamate
The most abundant free amino acid in the brain that is located at the
crossroad between multiple metabolic pathways; the principal excitatory
neurotransmitter in the brain.
Helicobacter pylori
A type of bacteria that causes infection in the stomach and is the main
causative factor of peptic ulcers, gastritis and stomach cancer.
Hippocampus
A complex brain structure rooted deep into the temporal lobe that has a
major role in learning and memory. It is a plastic and vulnerable structure
that gets damaged by a variety of stimuli.
Holter monitoring
Medical device that measures your heart's activity, such as rate and rhythm .
Hyperlipidemia
A term used to define the high levels of fat in the blood, such as cholesterol,
LDL and triglycerides.
Hypertension
Also named high blood pressure that can lead to severe health
complications and increase the risk of heart disease, stroke, and sometimes
death.
Hypochlorhydria
A condition where there is a lack of adequate stomach acid, i.e.,
hydrochloric acid (HCl) being secreted into the stomach.
Immune system
A complex network of cells and proteins that defends the body against
infection. The immune system keeps a record of every germ (microbe) it
has ever defeated, so it can recognise and destroy the microbe quickly if it
enters the body again.
Inflammatory bowel disease
An umbrella term used to describe disorders that involve chronic
inflammation of the digestive tract.
Insula
A small region of the cerebral cortex located deep within the lateral sulcus,
which is a large fissure that separates the frontal and parietal lobes from the
temporal lobe.
Involuntary muscles
A muscle that contracts without conscious control and is found in walls of
internal organs such as in the stomach, intestine, bladder, and blood vessels
(excluding the heart) smooth muscle.
Lactobacillus
A type of bacteria. Any long, slender, rod-shaped, anaerobic bacterium of
the genus Lactobacillus, that produces large amounts of lactic acid in the
fermentation of carbohydrates, especially in milk.
Lactobacillus rhamnosus
First isolated in 1983 and known to have a strong avidity for human
intestinal cells and can survive acid and bile environments. It is considered
one of the most studied probiotics, with research showing it could alleviate
rotavirus diarrhea in children, prevent atopic dermatitis, protect against
urinary tract infections, and improve symptoms of irritable bowel syndrome
.
Laparoscopy
A surgical operation in which a fiber-optic instrument is inserted through
the abdominal wall to view the organs in the abdomen or to permit a
surgical procedure.
Limbic system
Complex system of nerves and linkages in the brain, involving some areas
near the edge of the cortex concerned with instinct and mood that control
basic emotions such as fear, pleasure, anger and drives (hunger, sex,
dominance, care of offspring).
Locus cerulosis
A nucleus in the pons of the brainstem involved with physiological
responses to stress that are part of the reticular activating system.
Major depression
Also known as unipolar or major depressive disorder, characterized by a
persistent feeling of sadness, despondency, hopelessness or a lack of
interest in stimuli.
Medulla (oblongata)
The medulla oblongata or simply medulla is a long stem-like structure that
makes up part of the brainstem.
Microbiota
Microbiota are “ecological communities of commensals, symbiotic and
pathogenic microorganism” found in and on all multicellular organisms
from plants to animals.
Nervusfacialis
Cranial nerve that supplies facial muscles.
Nervusglossopharyngeus
Sensory nerve to the pharynx and back of the tongue; motor fibers innervate
muscles that elevate the pharynx and larynx; includes parasympathetic
fibers to the optic ganglion.
Nervus oculomotorius
Innervates the extrinsic muscles of the eye.
Neuropsychiatric
A branch of medicine that deals with mental disorders attributable to
diseases of the nervous system.
Neurotransmitters
A chemical messenger that carries, boosts, and balances signals between
neurons, or nerve cells, and other cells in the body. These chemical
messengers can affect a wide variety of both physical and psychological
functions, including heart rate, sleep, appetite, mood, and fear .
Norepinephrine
Also named as noradrenaline that is released predominantly from the ends
of sympathetic nerve fibres and that acts to increase the force of skeletal
muscle contraction and the rate and force of contraction of the heart.
Nucleus tractus solitarius
A series of only sensory nuclei (clusters of nerve cell bodies) forming a
vertical column of grey substance rooted in the medulla oblongata.
Obesity
Medical condition that occurs when a person carries excess weight or body
fat that might affect their health.
Oncogene
An oncogene is a gene that has the potential to cause cancer.
Orbitofrontal cortex
A prefrontal cortex region in the frontal lobes of the brain, which is
involved in the cognitive process of decision-making.
Parasympathetic nervous system
The rest and digest system, the parasympathetic system conserves energy as
it slows the heart rate, increases intestinal and gland activity, and relaxes
sphincter muscles in the gastrointestinal tract.
Palliative
Reducing the severity of; denoting the alleviation of symptoms without
curing the underlying disease.
Perioperative
The time period of a patient's surgical procedure. It commonly includes
ward admission, anesthesia, surgery, and recovery.
Pneumogastric nerve
A nerve that supplies the pharynx, larynx, lungs, heart, esophagus, stomach,
and most of the abdominal visceral organs.
Proto-oncogene
A normal gene which, when altered by mutation, becomes an oncogene that
can contribute to cancer.
Putative
Assumed to exist or have existed .
Pyloroplasty
Surgery to enlarge the opening in the lower part of the stomach so that
stomach contents can empty into the small intestine.
Raphe nuclei
Located midline in the brainstem throughout the midbrain, pons, and
medulla that contains primarily serotonergic neurons, which release
serotonin with autocrine and paracrine effects, as well as synaptic
connections.
Seizures
Unexpected and uncontrolled electrical disturbance in the brain that causes
changes in behavior, movements or feelings, and in levels of consciousness.
Serotonin
Also named 5-hydroxytryptamine that is a monoamine neurotransmitter. It
has a popular image as a contributor to feelings of well-being and
happiness.
Somatic nervous system
The part of the peripheral nervous system that is responsible for carrying
motor and sensory information both to and from the central nervous system.
Sub diaphragmatic
Situated, occurring, or performing below the diaphragm a subdiaphragmatic
abscess subdiaphragmatic vagotomy.
Subclavian artery
A pair of large arteries in the thorax that supplies blood to the thorax, head,
neck, shoulder and arms. Depending on the side of the body, it can have two
origins: the aortic arch on the left and the brachiocephalic trunk on the
right.
Supraventricular tachycardia
Abnormally rapid heart rhythm having an electropathologic substrate that
causes the heart to escalate to rates higher than 100 beats per minute.
Sympathetic nervous system
Part of the autonomic nervous system that activates what is often termed the
fight or flight response.
TNF-α (Tumour Necrosis Factor alpha)
An inflammatory cytokine produced by macrophages/monocytes during
acute inflammation and is responsible for a diverse range of signaling
events with the cells, leading to necrosis or apoptosis .
Trachea
Also known as the windpipe, is a tube about 4 inches long and less than an
inch in diameter in most people, roots just under the larynx (voice box) and
runs down behind the breastbone.
Tranceutical
(medicine) Penetrating, entering, or passing through the intact skin.
Tumorigenesis
Is the formation of a cancer, whereby normal cells are transformed into
cancer cells.
Vagal trunk
A branch of the vagus nerve that contributes to the esophageal plexus.
Vagatomy
A surgical operation in which one or more branches of the vagus nerve are
cut, typically to reduce excessive gastric secretion.
Vasomotor activity
Actions upon a blood vessel that alter its diameter. More specifically, it can
refer to vasodilator action and vasoconstrictor action.
Vena cava
The large vein that returns blood to the heart from the head, neck and both
upper limbs.
Visceral signals
Communication from the viscera to brain is continuous and pervasive.
Voluntary muscles
The muscles that are under conscious control and can be controlled at will
or we can choose when to use them.
 REFERENCES
SECTION 2
1 ​ Morris, G. L. & Mueller, W. M. Long-term treatment with vagus
nerve stimulation in patients with refractory epilepsy. Neurology 53 ,
1731-1731 (1999).
2 ​Fulton, J. F. Physiology of the nervous system, rev. (1938).
3 ​ Sarnat, H. G. & Netsky, M. G. Evolution of the nervous system .
(Oxford U. Press, 1974).
4 ​ Gershon, M. D. The enteric nervous system: a second brain.
Hospital Practice 34 , 31-52 (1999).
5 ​Furness, J. B. The enteric nervous system. (2006).
6 ​ Breit, S., Kupferberg, A., Rogler, G. & Hasler, G. Vagus Nerve as
Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory
Disorders. Frontiers in Psychiatry 9 , doi:10.3389/fpsyt.2018.00044
(2018).
7 ​ Berthoud, H.-R. & Neuhuber, W. L. Functional and chemical
anatomy of the afferent vagal system. Autonomic Neuroscience 85 ,
1-17 (2000).
8 ​ Handforth, A. et al. Vagus nerve stimulation therapy for partial-
onset seizures: a randomized active-control trial. Neurology 51 , 48-
55 (1998).
9 ​ Zope, S. A. & Zope, R. A. Sudarshan kriya yoga: Breathing for
health. International journal of yoga 6 , 4 (2013).
10 ​ Rush, A. J. et al. Vagus nerve stimulation (VNS) for treatment-
resistant depressions: a multicenter study. Biological psychiatry 47 ,
276-286 (2000).
SECTION 3
1 ​ Dragstedt, L. R. & Owens, F. M. Supra-Diaphragmatic Section of
the Vagus Nerves in Treatment of Duodenal Ulcer. Proceedings of
the Society for Experimental Biology and Medicine 53 , 152-154
(1943).
2 ​Rabben, H.-L., Zhao, C.-M., Hayakawa, Y., C Wang, T. & Chen, D.
Vagotomy and gastric tumorigenesis. Current neuropharmacology
14 , 967-972 (2016).
3 ​ Berthoud, H.-R. & Neuhuber, W. L. Functional and chemical
anatomy of the afferent vagal system. Autonomic Neuroscience 85 ,
1-17 (2000).
4 ​ Handforth, A. et al. Vagus nerve stimulation therapy for partial-
onset seizures: a randomized active-control trial. Neurology 51 , 48-
55 (1998).
5 ​ Camilleri, M. et al. Intra-abdominal vagal blocking (VBLOC
therapy): clinical results with a new implantable medical device.
Surgery 143 , 723-731 (2008).
6 ​ Berthoud, H.-R. The vagus nerve, food intake and obesity.
Regulatory Peptides 149 , 15-25, doi:
https://doi.org/10.1016/j.regpep.2007.08.024 (2008).
SECTION 4
1 ​ Rush, A. J. et al. Vagus nerve stimulation for treatment-resistant
depression: a randomized, controlled acute phase trial. Biological
psychiatry 58 , 347-354 (2005).
2 ​ Carpenter, L. L. et al. Effect of vagus nerve stimulation on
cerebrospinal fluid monoamine metabolites, norepinephrine, and
gamma-aminobutyric acid concentrations in depressed patients.
Biological Psychiatry 56 , 418-426 (2004).
3 ​ Rong, P.-J. et al. Transcutaneous vagus nerve stimulation for the
treatment of depression: a study protocol for a double blinded
randomized clinical trial. BMC complementary and alternative
medicine 12 , 255 (2012).
4 ​ Marangell, L. B. et al. Vagus nerve stimulation (VNS) for major
depressive episodes: one year outcomes. Biological psychiatry 51 ,
 280-287 (2002).
5 ​ Sackeim, H. A. et al. Vagus Nerve Stimulation (VNS™) for
Treatment-Resistant Depression: Efficacy, Side Effects, and
Predictors of Outcome. Neuropsychopharmacology 25 , 713-728,
doi: https://doi.org/10.1016/S0893-133X(01)00271-8 (2001).
6 ​ VNS therapy physician’s manual. Houston (TX): LivaNova PLC;
Available at: https://us.livanova.cyberonics.com/ , 2017).
7 ​George, M. S. et al. A pilot study of vagus nerve stimulation (VNS)
for treatment-resistant anxiety disorders. Brain stimulation 1 , 112-
121 (2008).
8 ​ Klarer, M. et al. Gut vagal afferents differentially modulate innate
anxiety and learned fear. Journal of Neuroscience 34 , 7067-7076
(2014).
9 ​ Bravo, J. A. et al. Ingestion of Lactobacillus strain regulates
emotional behavior and central GABA receptor expression in a
mouse via the vagus nerve. Proceedings of the National Academy of
Sciences 108 , 16050-16055 (2011).
10 ​ Field, T. Yoga clinical research review. Complementary therapies
in clinical practice 17 , 1-8 (2011) .
SECTION 5
1 ​ Fox, S. I. Human Physiology 9th Editon . (McGraw-Hill press,
New York, USA, 2006).
2 ​ Stevens, C. E. & Hume, I. D. Comparative physiology of the
vertebrate digestive system . (Cambridge University Press, 2004).
3 ​ Williams, E. K. et al. Sensory neurons that detect stretch and
nutrients in the digestive system. Cell 166 , 209-221 (2016).
4 ​ Berthoud, H. R., Jedrzejewska, A. & Powley, T. L. Simultaneous
labeling of vagal innervation of the gut and afferent projections from
the visceral forebrain with dil injected into the dorsal vagal complex
in the rat. Journal of comparative neurology 301 , 65-79 (1990).
5 ​ WINGATE, D. on Brain-Gut Interactions. Digestive Diseases and
Sciences 34 , 969-990 (1989).
6 ​ Gershon, M. D. The enteric nervous system: a second brain.
Hospital Practice 34 , 31-52 (1999).
7 ​ Cryan, J. F. & O’mahony, S. The microbiome‐gut‐brain axis: from
bowel to behavior. Neurogastroenterology & Motility 23 , 187-192
(2011).
8 ​ Cheadle, G. A., Costantini, T. W., Bansal, V., Eliceiri, B. P. &
Coimbra, R. Cholinergic signaling in the gut: a novel mechanism of
barrier protection through activation of enteric glia cells. Surgical
infections 15 , 387-393 (2014).
9 ​ Pavlov, V. A. & Tracey, K. J. The vagus nerve and the
inflammatory reflex—linking immunity and metabolism. Nature
Reviews Endocrinology 8 , 743 (2012).
10 ​ Goehler, L. E. et al. Vagal immune-to-brain communication: a
visceral chemosensory pathway. Autonomic Neuroscience 85 , 49-59
(2000).
11 ​ Gallowitsch-Puerta, M. & Pavlov, V. A. Neuro-immune
interactions via the cholinergic anti-inflammatory pathway. Life
Sciences 80 , 2325-2329 (2007).
12 ​ Bonaz, B., Sinniger, V. & Pellissier, S. Vagus nerve stimulation: a
new promising therapeutic tool in inflammatory bowel disease.
Journal of internal medicine 282 , 46-63 (2017).
13 ​ Bonaz, B. et al. Chronic vagus nerve stimulation in Crohn's
disease: a 6‐month follow‐up pilot study. Neurogastroenterology &
Motility 28 , 948-953 (2016).
14 ​ Hotamisligil, G. S. Inflammation and metabolic disorders. Nature
444 , 860 (2006).
15 ​Goldstein, I. M., Snyderman, R. & Gallin, J. I. Inflammation: basic
principles and clinical correlates . (Raven press, 1992).
16 ​ Levine, Y. A. et al. Neurostimulation of the cholinergic anti-
inflammatory pathway ameliorates disease in rat collagen-induced
arthritis. PloS one 9 , e104530, doi:10.1371/journal.pone.0104530
(2014).
17 ​ Patel, Y. A., Saxena, T., Bellamkonda, R. V. & Butera, R. J.
Kilohertz frequency nerve block enhances anti-inflammatory effects
of vagus nerve stimulation. Sci Rep 7 , 39810-39810,
doi:10.1038/srep39810 (2017).
18 ​ Koopman, F. A. et al. Vagus nerve stimulation inhibits cytokine
production and attenuates disease severity in rheumatoid arthritis.
Proceedings of the National Academy of Sciences 113 , 8284-8289,
doi:10.1073/pnas.1605635113 (2016).
SECTION 6
1 ​George, M. S. et al. A pilot study of vagus nerve stimulation (vagus
nerve stimulation) for treatment-resistant anxiety disorders. Brain
stimulation 1 , 112-121 (2008).
2 ​ O’Keane, V., Dinan, T. G., Scott, L. & Corcoran, C. Changes in
hypothalamic–pituitary–adrenal axis measures after vagus nerve
stimulation therapy in chronic depression. Biological psychiatry 58 ,
963-968 (2005).
3 ​ McKean, J., Naug, H., Nikbakht, E., Amiet, B. & Colson, N.
Probiotics and subclinical psychological symptoms in healthy
participants: a systematic review and meta-analysis. The Journal of
alternative and complementary medicine 23 , 249-258 (2017).
4 ​ Daban, C., Martinez-Aran, A., Cruz, N. & Vieta, E. Safety and
efficacy of Vagus nerve stimulation in treatment-resistant
depression. A systematic review. Journal of affective disorders 110 ,
1-15 (2008).
5 ​ Fornai, F., Ruffoli, R., Giorgi, F. S. & Paparelli, A. The role of
locus coeruleus in the antiepileptic activity induced by vagus nerve
stimulation. European Journal of Neuroscience 33 , 2169-2178
(2011).
6 ​ Rong, P. et al. Effect of transcutaneous auricular vagus nerve
stimulation on major depressive disorder: a nonrandomized
controlled pilot study. Journal of affective disorders 195 , 172-179
(2016).
7 ​Sackeim, H. A. et al. Durability of antidepressant response to vagus
nerve stimulation (vagus nerve stimulation™). International Journal
of Neuropsychopharmacology 10 , 817-826 (2007).
8 ​ Sackeim, H. A. et al. Vagus nerve stimulation (vagus nerve
stimulation™) for treatment-resistant depression: efficacy, side
effects, and predictors of outcome. Neuropsychopharmacology 25 ,
713-728 (2001).
SECTION 7
1 ​Maturana, H. R. Neurophysiology of cognition. (1970).
2 ​ Clark, K. B., Naritoku, D. K., Smith, D. C., Browning, R. A. &
Jensen, R. A. Enhanced recognition memory following vagus nerve
stimulation in human subjects. Nature neuroscience 2 , 94 (1999).
3 ​ Helmstaedter, C., Hoppe, C. & Elger, C. E. Memory alterations
during acute high-intensity vagus nerve stimulation. Epilepsy
research 47 , 37-42 (2001).
4 ​ Zovkic, I. B., Guzman-Karlsson, M. C. & Sweatt, J. D. Epigenetic
regulation of memory formation and maintenance. Learning &
memory 20 , 61-74 (2013).
5 ​ Qian, Y. et al. Effect of α7nAChR mediated cholinergic anti-
inflammatory pathway on inhibition of atrial fibrillation by low-level
vagus nerve stimulation. Zhonghua yi xue za zhi 98 , 855-859
(2018).
6 ​Vonck, K. et al. Vagus nerve stimulation… 25 years later! What do
we know about the effects on cognition? Neuroscience &
Biobehavioral Reviews 45 , 63-71 (2014).
7 ​ Huffman, W. J. et al. Modulation of neuroinflammation and
memory dysfunction using percutaneous vagus nerve stimulation in
mice. Brain stimulation 12 , 19-29 (2019).
8 ​Dodrill, C. B. & Morris, G. L. Effects of vagal nerve stimulation on
cognition and quality of life in epilepsy. Epilepsy & Behavior 2 , 46-
53 (2001).
9 ​Nierenberg, A. A., Alpert, J. E., Gardner-Schuster, E. E., Seay, S. &
Mischoulon, D. Vagus Nerve Stimulation: 2-Year Outcomes for
Bipolar Versus Unipolar Treatment-Resistant Depression. Biological
Psychiatry 64 , 455-460, doi:
https://doi.org/10.1016/j.biopsych.2008.04.036 (2008).
10 ​ Marangell, L. B. et al. A 1-year pilot study of vagus nerve
stimulation in treatment-resistant rapid-cycling bipolar disorder. The
Journal of clinical psychiatry 69 , 183-189 (2008).
11 ​ Klarer, M. et al. Gut vagal afferents differentially modulate innate
anxiety and learned fear. Journal of Neuroscience 34 , 7067-7076
(2014).
12 ​ Merrill, C. A. et al. Vagus nerve stimulation in patients with
Alzheimer's disease: Additional follow-up results of a pilot study
through 1 year. The Journal of clinical psychiatry (2006).
SECTION 8
1 ​ Gerritsen, R. J. S. & Band, G. P. Breath of life: the respiratory
vagal stimulation model of contemplative activity. Frontiers in
human neuroscience 12 , 397 (2018).
2 ​ Ulloa, L. The vagus nerve and the nicotinic anti-inflammatory
pathway. Nature Reviews Drug Discovery 4 , 673 (2005).
3 ​ Borovikova, L. V. et al. Role of vagus nerve signaling in CNI-
1493-mediated suppression of acute inflammation. Autonomic
Neuroscience 85 , 141-147, doi: https://doi.org/10.1016/S1566-
0702(00)00233-2 (2000).
SECTION 9
1 ​ Ejskjaer, N. et al. Prevalence of autoantibodies to autonomic
nervous tissue structures in type 1 diabetes mellitus. Diabetic
medicine 16 , 544-549 (1999).
2 ​ Yoshida, M. M., Schuffler, M. D. & Sumi, S. M. There are no
morphologic abnormalities of the gastric wall or abdominal vagus in
patients with diabetic gastroparesis. Gastroenterology 94 , 907-914
(1988).
3 ​ Fontanesi, L. B., Ferrão, A. C. M., Neri, L. O. & Fazan, V. P. S.
Morphological and morphometric study of the cervical vagus nerve
myelinated fibers in acute and chronic experimental diabetes. The
FASEB Journal 32 , 781.711-781.711 (2018).
4 ​ Wu, S.-C. et al. Association of vagus nerve severance and
decreased risk of subsequent type 2 diabetes in peptic ulcer patients:
An Asian population cohort study. Medicine 95 (2016).
5 ​ Yuan, H. & Silberstein, S. D. Vagus nerve and vagus nerve
stimulation, a comprehensive review: part II. Headache: The
Journal of Head and Face Pain 56 , 259-266 (2016).
6 ​ Kagihara, J., Fujii-Lau, L. & Lopez, K. Gastroparesis Caused by
Vagal Nerve Injury Following Radiofrequency Catheter Ablation for
Atrial Fibrillation: 2206. American Journal of Gastroenterology 111
, S1057 (2016).
7 ​ Jacobs, V. et al. Vagus nerve injury symptoms after catheter
ablation for atrial fibrillation. Pacing and Clinical Electrophysiology
41 , 389-395 (2018).
SECTION 10
1 ​ Ejskjaer, N. et al. Prevalence of autoantibodies to autonomic
nervous tissue structures in type 1 diabetes mellitus. Diabetic
medicine 16 , 544-549 (1999).
2 ​ Yoshida, M. M., Schuffler, M. D. & Sumi, S. M. There are no
morphologic abnormalities of the gastric wall or abdominal vagus in
patients with diabetic gastroparesis. Gastroenterology 94 , 907-914
(1988).
3 ​ Fontanesi, L. B., Ferrão, A. C. M., Neri, L. O. & Fazan, V. P. S.
Morphological and morphometric study of the cervical vagus nerve
myelinated fibers in acute and chronic experimental diabetes. The
FASEB Journal 32 , 781.711-781.711 (2018).
4 ​ Wu, S.-C. et al. Association of vagus nerve severance and
decreased risk of subsequent type 2 diabetes in peptic ulcer patients:
An Asian population cohort study. Medicine 95 (2016).
5 ​ Yuan, H. & Silberstein, S. D. Vagus nerve and vagus nerve
stimulation, a comprehensive review: part II. Headache: The
Journal of Head and Face Pain 56 , 259-266 (2016).
6 ​ Kagihara, J., Fujii-Lau, L. & Lopez, K. Gastroparesis Caused by
Vagal Nerve Injury Following Radiofrequency Catheter Ablation for
Atrial Fibrillation: 2206. American Journal of Gastroenterology 111
, S1057 (2016).
7 ​ Jacobs, V. et al. Vagus nerve injury symptoms after catheter
ablation for atrial fibrillation. Pacing and Clinical Electrophysiology
41 , 389-395 (2018).
8 ​ Weinberg, J. A., Stempien, S. J., Movius, H. J. & Dagradi, A. E.
Vagotomy and pyloroplasty in the treatment of duodenal ulcer. The
American Journal of Surgery 92 , 202-207 (1956).
9 ​ Green, R., Kara, N. & Cocks, H. Vitamin B 12 deficiency: an
unusual cause of vocal fold palsy. The Journal of Laryngology &
Otology 125 , 1309-1311 (2011).
10 ​ Oh, R. & Brown, D. L. Vitamin B12 deficiency. American family
physician 67 , 979-986 (2003).
11 ​ Tassorelli, C. et al. Noninvasive vagus nerve stimulation as acute
therapy for migraine: The randomized PRESTO study. Neurology 91
, e364-e373 (2018).
12 ​Silberstein, S. D. et al. Chronic migraine headache prevention with
noninvasive vagus nerve stimulation: The EVENT study. Neurology
87 , 529-538 (2016).
13 ​ Straube, A., Ellrich, J., Eren, O., Blum, B. & Ruscheweyh, R.
Treatment of chronic migraine with transcutaneous stimulation of
the auricular branch of the vagal nerve (auricular t-VNS): a
randomized, monocentric clinical trial. The journal of headache and
pain 16 , 63 (2015).
14 ​ Greenwood, B. & Mantle, M. Mucin and protein release in the
rabbit jejunum: effects of bethanechol and vagal nerve stimulation.
Gastroenterology 103 , 496-505 (1992).
15 ​ Hornby, P. J. & Abrahams, T. P. Central control of lower
esophageal sphincter relaxation. The American journal of medicine
108 , 90-98 (2000).
16 ​ Hsieh, T., Chen, M., McAfee, A. & Kifle, Y. Sleep-related
breathing disorder in children with vagal nerve stimulators.
Pediatric neurology 38 , 99-103 (2008).
17 ​ LeBlanc, J., Dulac, S., Cote, J. & Girard, B. Autonomic nervous
system and adaptation to cold in man. Journal of Applied Physiology
39 , 181-186 (1975).
18 ​Gupta, B., Nier, K. & Hensel, H. Cold-sensitive afferents from the
abdomen. Pflügers Archiv 380 , 203-204 (1979).
19 ​ Tyler, R. et al. Vagus nerve stimulation paired with tones for the
treatment of tinnitus: a prospective randomized double-blind
controlled pilot study in humans. Scientific reports 7 , 11960 (2017).
SECTION 11
1 ​ Malow, B., Edwards, J., Marzec, M., Sagher, O. & Fromes, G.
Effects of vagus nerve stimulation on respiration during sleep: a
pilot study. Neurology 55 , 1450-1454 (2000).
2 ​ Adrian, E. Afferent impulses in the vagus and their effect on
respiration. The Journal of physiology 79 , 332-358 (1933).
3 ​ Mitchell, R. A. & Berger, A. J. Neural regulation of respiration.
American Review of Respiratory Disease 111 , 206-224 (1975).
4 ​Caparso, A. et al. (Google Patents, 2011).
5 ​ Sovik, R. The science of breathing--the yogic view. Progress in
brain research 122 , 491-505, doi:10.1016/s0079-6123(08)62159-7
(2000).
6 ​Li, T. Y. & Yeh, M. L. [The application of qi-gong therapy to health
care]. Hu li za zhi The journal of nursing 52 , 65-70 (2005).
7 ​ Martarelli, D., Cocchioni, M., Scuri, S. & Pompei, P.
Diaphragmatic breathing reduces exercise-induced oxidative stress.
Evidence-Based Complementary and Alternative Medicine 2011
(2011).
SECTION 12
1 ​ Schiano, T. D. Treatment options for hepatic encephalopathy.
Pharmacotherapy: The Journal of Human Pharmacology and Drug
Therapy 30 , 16S-21S (2010).
2 ​ Wu, J. C. Psychological co-morbidity in functional gastrointestinal
disorders: epidemiology, mechanisms and management. Journal of
neurogastroenterology and motility 18 , 13 (2012).
3 ​Jangi, S. et al. Alterations of the human gut microbiome in multiple
sclerosis. Nature communications 7 , 12015 (2016).
4 ​ MacIntosh, C. G. et al. Effect of exogenous cholecystokinin
(CCK)-8 on food intake and plasma CCK, leptin, and insulin
concentrations in older and young adults: evidence for increased
CCK activity as a cause of the anorexia of aging. The Journal of
Clinical Endocrinology & Metabolism 86 , 5830-5837 (2001).
5 ​ Rogers, R. C. & Hermann, G. E. Mechanisms of action of CCK to
activate central vagal afferent terminals. Peptides 29 , 1716-1725
(2008).
6 ​Harro, J. CCK and NPY as anti-anxiety treatment targets: promises,
pitfalls, and strategies. Amino acids 31 , 215-230 (2006).
7 ​ Manning, T. S. & Gibson, G. R. Prebiotics. Best practice &
research clinical gastroenterology 18 , 287-298 (2004).
8 ​ De Vrese, M. & Schrezenmeir. in Food biotechnology 1-66
(Springer, 2008).
9 ​ Nicholson, J. K. et al. Host-gut microbiota metabolic interactions.
Science 336 , 1262-1267 (2012).
10 ​ Schippa, S. & Conte, M. P. Dysbiotic Events in Gut Microbiota:
Impact on Human Health. Nutrients 6 , 5786-5805 (2014).
11 ​ Roberfroid, M. B. Prebiotics and probiotics: are they functional
foods? The American journal of clinical nutrition 71 , 1682S-1687S
(2000).
12 ​Lee, Y. K. & Salminen, S. Handbook of probiotics and prebiotics .
(John Wiley & Sons, 2009).
13 ​ Hosoda, H., Kojima, M., Matsuo, H. & Kangawa, K. Ghrelin and
des-acyl ghrelin: two major forms of rat ghrelin peptide in
gastrointestinal tissue. Biochemical and biophysical research
communications 279 , 909-913 (2000).
14 ​ Date, Y. et al. The role of the gastric afferent vagal nerve in
ghrelin-induced feeding and growth hormone secretion in rats.
Gastroenterology 123 , 1120-1128 (2002).
SECTION 13
1 ​ Carrington, P. Freedom in meditation . (Anchor Press/Doubleday,
1977).
2 ​Moore, A. & Malinowski, P. Meditation, mindfulness and cognitive
flexibility. Consciousness and cognition 18 , 176-186 (2009).
3 ​ Wallace, R. K. Physiological effects of transcendental meditation.
Science 167 , 1751-1754 (1970).
4 ​ Donne, J. Meditation xvii. Devotions upon emergent occasions
1624 , 344-345 (1999).
5 ​ Marlatt, G. A. & Kristeller, J. L. Mindfulness and meditation.
(1999).
6 ​ Astin, J. A. Stress reduction through mindfulness meditation.
Psychotherapy and psychosomatics 66 , 97-106 (1997).
7 ​ Ditto, B., Eclache, M. & Goldman, N. Short-term autonomic and
cardiovascular effects of mindfulness body scan meditation. Annals
of Behavioral Medicine 32 , 227-234 (2006).
8 ​ Grossman, P. Mindfulness: awareness informed by an embodied
ethic. Mindfulness 6 , 17-22 (2015).
9 ​ Luders, E., Clark, K., Narr, K. L. & Toga, A. W. Enhanced brain
connectivity in long-term meditation practitioners. Neuroimage 57 ,
1308-1316 (2011).
10 ​ von Rhein, D. et al. The NeuroIMAGE study: a prospective
phenotypic, cognitive, genetic and MRI study in children with
attention-deficit/hyperactivity disorder. Design and descriptives.
European child & adolescent psychiatry 24 , 265-281 (2015).
11 ​ Krygier, J. R. et al. Mindfulness meditation, well-being, and heart
rate variability: a preliminary investigation into the impact of
intensive Vipassana meditation. International Journal of
Psychophysiology 89 , 305-313 (2013).
12 ​ Pardo, J. V. et al. Chronic vagus nerve stimulation for treatment-
resistant depression decreases resting ventromedial prefrontal
glucose metabolism. Neuroimage 42 , 879-889 (2008).
13 ​ Tang, Y.-Y., Hölzel, B. K. & Posner, M. I. The neuroscience of
mindfulness meditation. Nature Reviews Neuroscience 16 , 213-225
(2015).
14 ​ Eberth, J. & Sedlmeier, P. The Effects of Mindfulness Meditation:
A Meta-Analysis. Mindfulness 3 , 174-189, doi:10.1007/s12671-
012-0101-x (2012).
SECTION 14
1 ​ Dossey, L. Taking note: music, mind, and nature. Alternative
therapies in health and medicine 9 , 10 (2003).
2 ​Zealand, M. T. N. (Retrieved, 2009).
3 ​ Peters, J. S. Music therapy: An introduction . (Charles C Thomas,
Publisher, 1987).
4 ​ White, J. M. Effects of relaxing music on cardiac autonomic
balance and anxiety after acute myocardial infarction. American
Journal of Critical Care 8 , 220 (1999).
5 ​ Sim, C. S. et al. The effects of different noise types on heart rate
variability in men. Yonsei medical journal 56 , 235-243 (2015).
6 ​ McCraty, R., Barrios-Choplin, B., Atkinson, M. & Tomasino, D.
The effects of different types of music on mood, tension, and mental
clarity. Altern Ther Health Med 4 , 75-84 (1998).
7 ​Loewy, J., Stewart, K., Dassler, A.-M., Telsey, A. & Homel, P. The
Effects of Music Therapy on Vital Signs, Feeding, and Sleep in
Premature Infants. Pediatrics 131 , doi:10.1542/peds.2012-1367
(2013).
8 ​ Loewy, J. Music psychotherapy assessment. Music Therapy
Perspectives 18 , 47-58 (2000).
SECTION 15
1 ​Weinberg, L. P. & Levine, P. A. (Google Patents, 2005).
2 ​Boveja, B. R. & Widhany, A. (Google Patents, 2006).
3 ​ Ben‐Menachem, E., Revesz, D., Simon, B. & Silberstein, S.
Surgically implanted and non‐invasive vagus nerve stimulation: a
review of efficacy, safety and tolerability. European journal of
neurology 22 , 1260-1268 (2015).
4 ​ Giordano, F., Zicca, A., Barba, C., Guerrini, R. & Genitori, L.
Vagus nerve stimulation: Surgical technique of implantation and
revision and related morbidity. Epilepsia 58 , 85-90 (2017).
5 ​ Zambrelli, E. et al. Laryngeal motility alteration: A missing link
between sleep apnea and vagus nerve stimulation for epilepsy.
Epilepsia 57 , e24-e27 (2016).
6 ​ FDA. Premarket Approval (PMA) , <
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?
id=P970003 > (
7 ​Schachter, S. C. & Saper, C. B. Vagus nerve stimulation. Epilepsia
39 , 677-686 (1998).
8 ​ Henry, T. R. Therapeutic mechanisms of vagus nerve stimulation.
Neurology 59 , S3-S14 (2002).
9 ​ Kimberley, T. J. et al. Vagus nerve stimulation paired with upper
limb rehabilitation after chronic stroke: a blinded randomized pilot
study. Stroke 49 , 2789-2792 (2018).
10 ​ Kreuzer, P. M. et al. Feasibility, safety and efficacy of
transcutaneous vagus nerve stimulation in chronic tinnitus: an open
pilot study. Brain stimulation 7 , 740-747 (2014).
11 ​ Huang, F. et al. Effect of transcutaneous auricular vagus nerve
stimulation on impaired glucose tolerance: a pilot randomized study.
BMC complementary and alternative medicine 14 , 203,
doi:10.1186/1472-6882-14-203 (2014).
12 ​ Huang, J., Wang, Y., Jiang, D., Zhou, J. & Huang, X. The
sympathetic-vagal balance against endotoxemia. Journal of Neural
Transmission 117 , 729-735, doi:10.1007/ s00702-010-0407-6
(2010).
13 ​ Hasan, A. et al. Transcutaneous noninvasive vagus nerve
stimulation (tVNS) in the treatment of schizophrenia: a bicentric
randomized controlled pilot study. European archives of psychiatry
and clinical neuroscience 265 , 589-600 (2015).
14 ​ Kostov, K., Kostov, H. & Taubøll, E. Long-term vagus nerve
stimulation in the treatment of Lennox–Gastaut syndrome. Epilepsy
& Behavior 16 , 321-324 (2009).
15 ​ Johnson, R. L. & Wilson, C. G. A review of vagus nerve
stimulation as a therapeutic intervention. J Inflamm Res 11 , 203-
213, doi:10.2147/JIR.S163248 (2018).
 P.S.
If you liked this book and want to discover similar topics, feel free to write
a message with your name to this email:

E Mma@wisementorpress.com

and you will receive a preview of my future books for FREE.

If you want to apply for the exclusive facebook group, send us an email
with who you are and why you want to join the group to the email:
Fb.group@wisementorpress.com
 REVIEWS AND
FEEDBACK
Amazon reviews are very helpful and important to any author. If you enjoy
this book, it would be much appreciated if you could take a moment of your
time to share your positive opinions and post a review. It doesn’t have to be
very long. Just a rating and a few words are enough to leave a lasting
impression on future readers, who could also gain many benefits from the
knowledge shared here. Here is the link if you will have the pleasure to
leave us your thoughts on the book. We look forward to hearing from you!
Https://Amzn.to/3iUGUYC

For any general feedback about the book, please feel free to contact us at
this email:

Contact@wisementorpress.com

We love hearing from our readers!

 EXCLUSIVE COURSE FOR
READER S
Https://Emma.wisementorpress.com/Course1
 This le was downloaded from Z-Library project

Your gateway to knowledge and culture. Accessible for everyone.

z-library.se singlelogin.re go-to-zlibrary.se single-login.ru

O cial Telegram channel

Z-Access

https://wikipedia.org/wiki/Z-Library
ffi
fi