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Essentials of neuromodulation
Botulinum toxin A ¼ Neuromodulator
Botulinum toxin A ¼ BoNT A
BoNT A ¼ Botulinum toxin A
BT A¼BoNT A
BoNT A ¼ BT A
Botulinum toxin ¼ BTX
BTX ¼ Botulinum toxin
Botulinum toxin ¼ BoNT ¼ BTX
BoNT ¼ Botulinum toxin ¼ BTX
Gram + anerobic bacterium Botulinum toxin A ¼ BoNT A
BoNT A ¼ Gram + anerobic bacterium Botulinum toxin A
To streamline the terminology, Neuromodulator and BoNT-A will continuously
be utilized when referring to all of the FDA forms of Botulinum toxin A for esthetic
purposes. When there is a discussion of where Botulinum toxin comes from, BoNT
will continuously be used (Fig. 3.1; Table 3.1).
Neuromodulator/Neuromodulation Umbrella
All neuromodulators/neuromodulations are called
There are 4 main Botulinum toxin-A (BT-A-) drugs used in the U.S.
BOTOX® Cosmetic (onabotulinumtoxinA)
Dysport® (abobotulinumtoxinA)
Neuromodulator and Neuromodulation are interchangeable terms
Fig. 3.1 Neuromodulation umbrella.
Botulinum toxin-A (BT-A-)
BT-A
JEUVEAU (prabotulinumtoxinA-xvfs)
XEOMIN® (incobotulinumtoxinA)
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Table 3.1 FDA approved Botulinum toxin A.
Types of Botulinum toxin A (BoNT-A)
FDA approved in the United States
Trade name Generic name Abbreviation
Dysport AbobotulinumtoxinA ABO
Botox OnabotulinumtoxinA ONA
Jeuveau PrabotulinumtoxinA-xvfs PRAB
Xeomin IncobotulinumtoxinA INCO
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CHAPTER 4
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What is botulinum toxin
The question may have presented itself as to what a neuromodulator is and
how it works? BoNT-As are acetylcholine release inhibitors. However,
knowing that BoNT-As are acetylcholine release inhibitors is not enough
to thoroughly understand the mechanism of action of BoNT-As. To understand the acetylcholine release inhibitor concept, we must first begin to
understand the origination point of neuromodulators. That is to understand
botulinum toxin (BoNT)s as a whole.
Botulinum toxin is produced by the anaerobic Gram-positive spore-
forming bacteria of the genus Clostridium. It is a unique and complex mixture
of proteins that contain botulinum neuromodulation (BoNT) along with
several other non-toxic proteins. BoNTs are reportedly the most potent
toxins known to mankind and can cause botulism. Botulism will leave an
animal or human in a flaccid paralyzed state should it be ingested orally.
Ironically enough BoNT containing medicines are used in traditional medicine and cosmetic medicine safely and with great success without
completely paralyzing their host. Science has provided enough research
to narrow down and isolate BoNTs to be delivered precisely to avoid harming the host entirely and just causing temporary paralysis of targeted muscles
or muscle groups. One who contracts botulism does not inject it into their
muscles for wrinkle reduction; better yet, they consume it due to the contamination of a food source with Clostridium botulinum. Clostridium spores
can be found worldwide in food, soil, freshwater, saltwater, sediment,
and various animals’ intestinal tracts.
There is notably, seven serotypes of BoNT produced by different strands
of Clostridium botulinum A–G. Man kinds nervous system is susceptible to the
strands A, B, C, E, F, and G and unaffected by D. It is types A and B that is
widely used in clinical application due to the long-lasting effects compared
to other types. The following chapters will focus heavily on botulinum toxin
type A and briefly touch upon type B to learn esthetic medicine.
Essentials of Neuromodulation Copyright © 2021 Elsevier Inc.
https://doi.org/10.1016/B978-0-323-89920-8.00006-0 All rights reserved.
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Understanding the nervous system
To better understand how BoNT-A works is part of learning to become a
proficient and eventually excellent cosmetic injector. We all learn differently, so some sections of this book will be more manageable to digest than
others. The book is meant to be reread and used as a lifelong reference. For
those visual learners, it may be the pictures that are most beneficial, or for the
statisticians, the graphs and charts may be of most significant use in the
beginning. No matter the learning style or comfort level, all of the information provided in this book is necessary to achieve mastery in esthetic medicine. It will all begin to come together at some point. Please do not fret
when it does not seem to sink in the right out of the gate. Learning takes
time, exposure, practice, and lots of repetition.
Let us begin to understand the nervous system bit by bit to break down
the complete mechanism of action of BoNTs. The nervous system is a very
compartmentalized yet complex complete system. It is responsible for coordinating the human body’s internal actions, electrically, chemically, functionally, and sensory wise. Communicating messages chemically and
electrical are sent through the nervous system to connect the different body
systems. For example, if one has a bright light shown in their eyes, the light
triggers a response in the body via the nervous system to constrict the pupil
and excite the reflex to scowl. There is such a delicate balance of systems run
by the nervous system’s electrical and chemical signals.
There are two main nervous system divisions, the central nervous system
(CNS) and the peripheral nervous system (PNS). The CNS consists of the
brain and the spinal cord. The PNS includes the spinal nerves and the cranial
nerves and senses, such as taste, smell, vision, hearing, balance, and the autonomic nervous system (ANS). The ANS is further subdivided into two
groups called the sympathetic ANS and the parasympathetic ANS. The sympathetic nervous system is responsible for an individual’s fight or flight
response. The PNS is responsible for the bodies rest and digest, or feed
and breed as some refer to it. One can infer the PNS functions and develop
an understanding of what functions it is responsible for with the very mention of peripheral. Sensory and motor axons make up the majority of the
PNS function. The sympathetic nervous system excites the body as the
parasympathetic nervous system tries to restore harmony within the body.
Botulinum toxin action is primarily happening within the ANS.
Moving along to developing an understanding of BoNT-A’s action, it is
necessary to be specific within the nervous system and develop an understanding of the terminals and the chemical and electrical action. At the
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junction between the muscle and the nerve is a particular space where the
magic of BoNT-As occurs, and it is called the neuromuscular junction. Let
us move forward to the beginning, understanding the drug’s connection and
how it is working within the body to impact the muscles and the nervous
system.
As we were refreshed with the previous paragraphs’ nervous system
function, we were reminded that muscles are connected to the brain via
the nervous system’s route for communication. The nervous system is a
highly complex network of neurons. Neurons are long cells that pass the
information along using either electrical or chemical signals. Chemical signals pass between neurons and muscles through synapses. Synapses are considered special linking cells. Neurotransmitters such as acetylcholine are used
to pass the message along through the synapses. Bont-A works by blocking
the release of acetylcholine at the neuromuscular junction, thus preventing
the transmission of messages from the nervous system to the muscle.
Botulinum toxin injections do not cross the blood-brain barrier.
Its effect is only on the peripheral nerves, thus increasing its safety
profile.
Acetylcholine plays a vital role in the effect of BoNT-A. Therefore, providers must understand the role of acetylcholine in the use of BoNT-A. We
must continue to break down the nervous system’s function so that a complete understanding of the BoNTs’ mechanism of action can be concluded.
That leads us to break down the question of what is acetylcholine? If BoNT
is an acetylcholine release inhibitor, we now need to understand acetylcholine’s role within the nerve. Acetylcholine acts to transmit nerve impulses
within the parasympathetic nervous system. Remember that the parasympathetic nervous system is a part of the autonomic nervous system. The autonomic nervous system is responsible for the induction of secretion, contracts
smooth muscles, and dilates blood vessels.
Acetylcholine is a neurotransmitter housed at the neuromuscular junction. It is stored at the end of the neuron tucked inside of a vesicle. The process of muscle movement occurs due to the snare complex that occurs once a
message is received. There are three main proteins involved in the snare
complex; Syntavin (connects to the nerve membrane), Synaptobrevin (connects to the vesicles), and Snap-25 (helps the other proteins link up). These
proteins join together to cause the vesicle to move toward the nerve membranes in order for fusion to occur. Then the acetylcholine can be released
across the synapses and passes to the muscle fibers. Now, the muscles will
contract and shorten in the face of the message being received.
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Mechanism of action of BoNT-A
Now that we understand that botulinum toxin A is an acetylcholine release
inhibitor, we can move forward with our learning. BoNT-A is a neuromuscular blocking agent used for the temporary improvement of dynamic rhytids.
Having gained the knowledge that BoNTs are neuromuscularblockingagents
will have great value regardingproper medical history and patient selection for
esthetic injections with BoNTs. BoNT-A and BoNT-E work by cleaving the
synaptosome-associated protein (SNAP-25), a presynaptic membrane protein
required for the fusion of neurotransmitter-containing vesicles.
Botulinum toxin A rapidly binds with the neuron membrane, and then it
splits into the active light chain and a heavy chain. Botulinum toxin A has a
high affinity to cleave snap 25. The affinity to cleave snap 25 prevents the
SNARE proteins from binding so that acetylcholine can not reach or pass
through the neuron membrane. Therefore, the acetylcholine does not reach
the muscle, thus inhibiting the muscle from contracting, causing a neuromuscular blocking effect. BONT’s direct effect is the inhibition of the cholinergic autonomic innervation of the exocrine glands and smooth muscles.
This mechanism of action has laid the foundation for the development of
the toxin as a therapeutic tool in esthetic medicine and several other fields of
medicine related to neuromuscular disorders.
Step by step on how BoNT-A work
It is suggested that there are three phases in the BoNT process:
Phase 1: Binding
Phase 2: Internalization
Phase 3: Blockade
1. BoNT-A is injected into the muscle.
2. The accessory proteins are disassociated from the BoNT-A via the action
of proteases.
3. The active chain is released.
4. Phase 1 is called the binding phase. The binding phase is when the active
BoNT is bound to the peripheral cholinergic nerve terminals within the
neuromuscular junction with a high affinity and specificity.
5. Then internalization occurs where the BoNT-A molecule is in the nerve
terminal through receptor-mediated endocytosis. This is considered to
be Phase 2 of the internalization process.
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6. The light chain is released into the cytoplasm. The dissociation of the
disulfide bond accompanies the release of the light chain.
7. The light chain performs its metalloproteinase activity that regulates the
exocytosis of acetylcholine vesicles. The targets are the Snare complex.
8. Phase 3 is the blockade phase. The blockade phase is when Snap 25 is
now cleaved, thus blocking the release of acetylcholine. Cleavage of the
snare proteins (the light chain cleaves SNAP-25), which results in the
blockade of neurotransmitter release and, therefore, neuroparalysis. This
inhibition of the synaptic exocytosis and incapacitated neuronal
transmission blocks the release of acetylcholine at the neuromuscular
junction, which directly blocks the muscular contraction.
9. Now the muscle can not contract as the message delivery system has been
shut down with the inhibition of acetylcholine release (Fig. 4.1).
Fig. 4.1 As seen in this photo, the presynaptic membrane releases the acetylcholine
down to the acetylcholine receptor in the muscles. The release of acetylcholine
allows the muscle to contract. Once acetylcholine is blocked from being released,
the receptor is not infused with acetylcholine, thus prohibiting the message of
contractility to occur within the muscle.
What we have at the end of this process is chemical denervation.
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Nerve terminal with release of acetylcholine
Some may still be asking what the previous chapter meant … Essentially,
BoNT-A works on muscles by inhibiting the muscles motions due to interference with the nervous systems’ chemical reaction. The primary effect of
BoNT-A is on the nerve, and the secondary effect is on the muscle; the last
effect is on the skin. Alternatively, shall we say the last effect is on the
patient’s mood because after the BoNT-A has taken effect, they love their
results and reflection, promoting a happy mood. When the muscle can not
compress and squeeze the skin, it does not weaken the elastin, collagen, and
hyaluronic acid, thus preventing the onset of the deep-set at rest lines (otherwise known as static rhytids) and wrinkles seen on the aging face. When
BoNT-A is injected into the muscle, the muscle remains in working order
while the nerves impulse is paused.
To break it down even further and put it in layman terms, BoNT-A disrupts the communication between one’s emotion, and the muscle, along
with the nervous system. It is said to decrease the muscle’s action potential.
If one is feeling disgruntled, it may be common to furrow the brows based
on that emotion. When a patient has had a neuromodulator injected into the
muscle between the brows where the physical manifestation of emotion may
show up, the ability to furrow will be diminished. The decrease in animation
is because the neuromodulator impedes the muscle’s ability to respond to the
emotion as the nervous system has been temporarily disabled. The results are
temporary and are a reversible inhibition of neurotransmitter release.
Botulinum toxin A takes approximately one and a half to two hours to
bind to the nerve. The paresis effect occurs over the next 2–7 days after
injections, peaking at about 7–10 days. Completing the nerve impulse
impedance occurs at 2 weeks. At this time is when a touchup or retreatment
is appropriate. No matter how much the patient begs and pleads, DO NOT
retreat before 2 weeks. The rule of 2 weeks is due to the incomplete mechanism of action before 2 weeks time frame. If the patient has retreated before
the 2-week mark, an unintended result may ensue.
The medication peaks at about 6 weeks and will start to decline slowly
until full reinnervation is restored. Reinnervation is when a slight movement is becoming noticeable again in the previously treated areas with
BoNT-A. The decline of the medication’s effect varies; however, it is typically noted to remain in effect for 3–4 months. It has been reported to last
6–12 months; however, this is rare. At which time, muscle movement will
begin to return.
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The recovery of one’s ability to furrow or squint again will return, typically 3–4 months post-treatment with BoNT-A. Recovery occurs through
proximal axonal sprouting and muscle reinnervation by the formation of a
new temporary neuromuscular junction. Eventually, the original neuromuscular junction regenerates. The recovery phase happens in two stages. The
first stage involves exocytosis, meaning the nerves resprout, which aids in
the neurons’ recovery. The second phase is the sprouts regress, and the
original terminal is restored. BoNT-A is entirely reversible with time making
it extremely safe as a therapeutic and or cosmetic therapy. Reports are
reproducible in that there is no atrophy in the nerve endings upon blockade
of neurotransmitter even in the face of repeat treatments (Dolly & Aoki,
2006).
The onset of action is one and a half hours to bind to the nerve.
The onset of clinical results is 2–7 days.
The final chemical denervation is 14 days.
Duration for facial esthetics is 6–12 weeks (product and dose vary).
Duration for hyperhidrosis is 6–9 months.
Review of the variety of BoNT-As commercially available
in the United States
BoNT-A products have several variations in preparation, which means they
are not necessarily interchangeable, and their intended use must be modified
based on product choice, reconstitution, and the intended esthetic goal. The
dose and volume play a role in the outcomes in the neuromodulation treatment (in other words, the volume of reconstitution of the product).
Currently, the US FDA has four approved products on the mainstream market in cosmetic practice.
1. Botox Cosmetic is the trade name for onabotulinumtoxinA and is a pre-
scription drug made by Allergan. BOTOX Cosmetic (onabotulinum-
toxinA) is indicated in adult patients for the temporary improvement
in the appearance of:
(i) Moderate to severe glabellar lines associated with corrugator and
procerus muscle activity.
(ii) Moderate to severe lateral canthal lines associated with orbicularis
oculi activity.
(iii) Moderate to severe forehead lines associated with frontalis activity.
Allergan (2020) (https://www.botoxcosmetic.com/what-is-
botox-cosmetic/botox-cosmetic-history)
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