toxins

Review
Anatomical Proposal for Botulinum Neurotoxin Injection for
Glabellar Frown Lines
Kyu-Ho Yi 1,2 , Ji-Hyun Lee 2 , Hye-Won Hu 2 and Hee-Jin Kim 2,3, *

1 COVID-19 Division, Wonju Public Health Center, Wonjusi 26493, Korea; kyuho90@korea.kr
2 Division in Anatomy and Developmental Biology, Department of Oral Biology, Human Identification
Research Institute, BK21 PLUS Project, College of Dentistry, Yonsei University, 50-1 Yonsei-ro,
Seoul 03722, Korea; jh_anatomy@yuhs.ac (J.-H.L.); wonhuh@yuhs.ac (H.-W.H.)
3 Department of Materials Science and Engineering, College of Engineering, Yonsei University,
Seoul 03722, Korea
* Correspondence: hjk776@yuhs.ac

Abstract: Botulinum neurotoxin injection for treating glabellar frown lines is a commonly used
method; however, side effects, such as ptosis and samurai eyebrow, have been reported due to a
lack of comprehensive anatomical knowledge. The anatomical factors important for the injection
of the botulinum neurotoxin into the corrugator supercilii muscle has been reviewed in this study.
Current understanding on the localization of the botulinum neurotoxin injection point from newer
anatomy examination was evaluated. We observed that for the glabellar-frown-line-related muscles,
the injection point could be more accurately demarcated. We propose the injection method and the
best possible injection sites for the corrugator supercilii muscle. We propose the optimal injection
sites using external anatomical landmarks for the frequently injected muscles of the face to accelerate
effective glabellar frown line removal. Moreover, these instructions would support a more accurate
procedure without adverse events.

Keywords: corrugator supercilii muscle; botulinum neurotoxin; glabellar frown line; facial wrinkle;



injection point; ptosis; samurai eyebrow


Citation: Yi, K.-H.; Lee, J.-H.; Hu,
Key Contribution: The research proposes a guide for effective botulinum neurotoxin injection for
H.-W.; Kim, H.-J. Anatomical
the corrugator supercilii muscle.
Proposal for Botulinum Neurotoxin
Injection for Glabellar Frown Lines.
Toxins 2022, 14, 268. https://doi.org/
10.3390/toxins14040268
1. Introduction
Received: 10 March 2022
The botulinum neurotoxin (BoNT) mechanism of action works by binding presynapti-
Accepted: 6 April 2022
cally to a high-affinity protein receptor and polysialogangliosides on the cholinergic nerve
Published: 10 April 2022
terminals, then entering the neuron and causing a sustained inhibition of synaptic trans-
Publisher’s Note: MDPI stays neutral mission [1,2]. Clinically, BoNT is aesthetically used for removing facial lines, as it relaxes
with regard to jurisdictional claims in the muscles used in facial expression. However, the glabella frown line is of more concern
published maps and institutional affil- to many individuals (Figure 1).
iations. Glabellar frown lines are created by three muscles: the corrugator supercilii (CSM),
procerus and depressor supercilii muscles; however, the most involved muscle is the
CSM. The superomedial fibers of the orbicularis oculi, otherwise known as the depressor
supercilii, are interconnected with the CSM and procerus muscles (Figure 2).
Copyright: © 2022 by the authors.
Side effects of BoNT injection in facial muscles, such as ptosis and samurai eyebrows,
Licensee MDPI, Basel, Switzerland.
This article is an open access article
have been reported to be due to lack of subtle anatomical information. Although suscepti-
distributed under the terms and
bility to BoNT varies among individuals, there is no efficient cure for ptosis, which lasts
conditions of the Creative Commons
for several months. Consequently, a safer method is to begin the primary treatment at a
Attribution (CC BY) license (https:// lower dosage. If the desired outcomes are not achieved, an additional touchup treatment
creativecommons.org/licenses/by/ could follow.
4.0/).

Toxins 2022, 14, 268. https://doi.org/10.3390/toxins14040268 https://www.mdpi.com/journal/toxins

Toxins 2022, 14, x FOR PEER REVIEW 2 of 9
Toxins 2022, 14, 268 2 of 8

Figure 1. Schematic image of the glabellar frown lines (GFL).

Glabellar frown lines are created by three muscles: the corrugator supercilii (CSM),
procerus and depressor supercilii muscles; however, the most involved muscle is the
CSM. The superomedial fibers of the orbicularis oculi, otherwise known as the depressor
supercilii, are interconnected with the CSM and procerus muscles (Figure 2).
Figure 1. Schematic image of the glabellar frown lines (GFL).
Figure 1. Schematic image of the glabellar frown lines (GFL).

Glabellar frown lines are created by three muscles: the corrugator supercilii (CSM),
procerus and depressor supercilii muscles; however, the most involved muscle is the
CSM. The superomedial fibers of the orbicularis oculi, otherwise known as the depressor
supercilii, are interconnected with the CSM and procerus muscles (Figure 2).

Figure 2. Schematic image of the corrugator supercilii (CSM), procerus (P) and depressor supercilii
Figure 2. Schematic image of the corrugator supercilii (CSM), procerus (P) and depressor supercilii
(DS) muscles. Glabellar frown lines are produced by three muscles; however, the most involved
(DS) muscles. Glabellar frown lines are produced by three muscles; however, the most involved
muscle
muscle is the CSM.is the CSM.

Subsequently, a modified dosage may be applied for each treatment. While injecting
Side effects of BoNT injection in facial muscles, such as ptosis and samurai eyebrows,
BoNT into the CSM, anatomical structures should be meticulously understood to prevent
have been reported to be due to lack of subtle anatomical information. Although suscep-
side effects, such as undesirable palsy of adjoining muscles, which may result in ptosis and
tibility to BoNT varies among individuals, there is no efficient cure for ptosis, which lasts
samurai eyebrow
image [3–5]. Ptosis maysupercilii
occur as the BoNT diffuses intodepressor
the levator palpebrae su-
for Figure
several2.months.
Schematic of the corrugator
Consequently, a safer method is(CSM), to beginprocerus (P) and
the primary treatmentsupercilii
at a
(DS) perioris
muscles. muscle, following injection into the CSM. Consequently, the dose must be adjusted
lower dosage. If Glabellar frown
the desired lines areare
outcomes produced by threeanmuscles;
not achieved, however,
additional touchupthe most involved
treatment
based on
muscle is the CSM. the muscle area of the person to prevent the severe side effects mentioned above.
could follow.
Furthermore, increased doses and repeated injections of BoNT produce antibodies,
Subsequently,
leading toaof
modified dosage
unsatisfactory may be applied for
treatment each treatment. While injecting
Side effects BoNT injection in facialoutcomes
muscles, [6–9].
such asVarious
ptosis studies relating
and samurai BoNT injection
eyebrows,
BoNT intopoints
the CSM, anatomical
to specific structures should be meticulously understood to prevent
have been reported to bemuscle
due toanatomy have already
lack of subtle anatomicalbeeninformation.
published [10].
Although suscep-
side effects, suchThisasstudy
undesirable
aimed palsy
to of adjoining
suggest safe and muscles, which may resultpoints
in ptosis
tibility to BoNT varies among individuals, there is effective
no efficientBoNT
cureinjection
for ptosis, which and injective
lasts
methods
for several for the
months. CSM of glabellar
Consequently, frown
a safer methodlines.is to begin the primary treatment at a
lower dosage. If the desired outcomes are not achieved, an additional touchup treatment
2. Anatomy of the CSM
could follow.
The CSM,
Subsequently, originating
a modified in themay
dosage superomedial
be appliedpart of thetreatment.
for each bony orbital rim,injecting
While passes supero-
laterally at an angle of 30 ◦ , and runs to the middle of the eyebrow, attaching to the dermal
BoNT into the CSM, anatomical structures should be meticulously understood to prevent
layer of
side effects, theasskin
such [11]. The palsy
undesirable CSM of liesadjoining
under the frontaliswhich
muscles, muscle as result
may it originates from the
in ptosis
frontal bone.
 methods for the CSM of glabellar frown lines.

2. Anatomy of the CSM

The CSM, originating in the superomedial part of the bony orbital rim, passes super-
olaterally at an angle of 30°, and runs to the middle of the eyebrow, attaching to the dermal
Toxins 2022, 14, 268 3 of 8
layer of the skin [11]. The CSM lies under the frontalis muscle as it originates from the
frontal bone.
Specifically, the CSM originates from about 16 mm above the horizontal intercanthal
plane (HL) and Specifically,
4–14 mm from the the
CSM originates
midline, frominto
inserts about
the 16 mm above
dermis theabove
(30 mm horizontal
the HLintercanthal
plane (HL) and 4–14 mm from the midline, inserts into the dermis (30 mm
and 16–35 mm from the midline), and interlinks into the frontalis muscle (Figure 3) [11]. above the HL
and 16–35 mm from the midline), and interlinks into the frontalis muscle (Figure 3) [11].

Figure 3. The corrugator supercilii muscle originates from 16 mm above the horizontal intercanthal
Figure 3. The corrugator
plane supercilii
(HL) and 4–14 mm muscle
fromoriginates from
the midline 16 mm
(ML), above
inserts intothe
thehorizontal
dermis (30intercanthal
mm above the HL and
Toxins 2022, 14, x FOR PEER REVIEW 16–35 mm from the midline), and interlinks with the frontalis muscle.above the HL and 4 of 9
plane (HL) and 4–14 mm from the midline (ML), inserts into the dermis (30 mm
16–35 mm from the midline), and interlinks with the frontalis muscle.
The vertical length of the CSM in Asians (15 mm) is shorter than that in Caucasians
The vertical
(21 mm) length
[11]. of
Thethe CSM
CSM in Asians
consists (15 muscle
of two mm) is bellies:
shorter oblique
than thatand
in Caucasians
transverse bellies [11].
(21 mm) [11]. The CSM consists of two muscle bellies: oblique and transverse bellies [11]. However,
The oblique belly runs vertically, whereas the transverse belly runs horizontally.
The oblique belly
there areruns
twovertically, whereas
types of oblique the transverse
bellies: narrow and belly runs
broad horizontally.
(Figure 4). How-
ever, there are two types of oblique bellies: narrow and broad (Figure 4).

Figure 4. The corrugator supercilii muscle has an oblique belly (orange-colored) and a transverse
belly (red-colored). The oblique belly has two types: the narrow type (a) and the broad type (b).

Figure 4.The
The oblique belly
corrugator of the narrow
supercilii type
muscle has anextends
oblique in a narrow
belly rectangular
(orange-colored) andshape [11]. This
a transverse
type
belly of belly merges
(red-colored). with the
The oblique frontalis
belly has twomuscle within
types: the thetype
narrow medial third
(a) and ofbroad
the the transverse
type (b). belly.
The broad type is triangular, covering most of the transverse belly superficially. The broad
The oblique
oblique belly of
belly tends tothe narrow
develop typepowerful
more extends in a narrow
muscle rectangular
contractions shape
of the [11]. This
eyebrow above
type ofmid
the belly merges line.
pupillary with However,
the frontalis
twomuscle within
types of the muscle
the CSM medial are
third of the to
difficult transverse
distinguish
belly.
andThethebroad typepoints
injection is triangular,
for two covering
types aremost of the
exactly the transverse
same. belly superficially. The
broad oblique
The CSM belly tends
pulls thetoeyebrows
develop more powerful
downward andmuscle
mediallycontractions of thevertical
and produces eyebrow lines
while
above thefrowning [12]. Ifline.
mid pupillary the CSM is paralyzed,
However, effacement
two types of the CSMof the glabellar
muscle arelines and to
difficult widening
dis-
of theand
tinguish eyebrows are observed.
the injection points for two types are exactly the same.
The CSM pulls the eyebrows downward and medially and produces vertical lines
3. Proposed
while frowning Injection
[12]. If theTechniques
CSM is paralyzed, effacement of the glabellar lines and widen-
ing of the The glabellarare
eyebrows muscles are not apart from each other; instead, these muscles are inter-
observed.
connected [11]. Consequently, the BoNT injected into the CSM may diffuse to the nearby
3. Proposed Injection Techniques
The glabellar muscles are not apart from each other; instead, these muscles are inter-
connected [11]. Consequently, the BoNT injected into the CSM may diffuse to the nearby
muscles. It is proposed that an injection be administered at four points: medial and lateral
 Toxins 2022, 14, 268 4 of 8

muscles. It is proposed that an injection be administered at four points: medial and lateral
points [13].
BoNT was injected into the medial and lateral points of the CSM, as shown in a
standard form; for the medial injection, the needle was advanced deeply until it touched the
periosteum, withdrawn 2–3 mm, followed by slow injection of BoNT into the muscle [13].
A Subdermal injection is preferable for the lateral points, and it is recommended to press
the frontal notch with fingers while injecting to avoid the inflow of BoNT into the orbital
cavity [14]. Additionally, the injection needle should point upward.
FOR PEER REVIEW A total of 6 U is injected; 1.5 U into each medial and lateral point [14]. The5medial
of 9
point is an interciliary point located on the frontal notch that can be palpated. The lateral
point is the crossing point of the mid-pupillary line and superciliary arch (Figure 5).

Figure 5. Guidance for injecting

Figure 5. Guidance botulinum
for injectingneurotoxin into the corrugator
botulinum neurotoxin supercilii
into the corrugator muscle.
supercilii A total
muscle. A total
of 6 U is injected; each
of 6 Umedial and
is injected; lateral
each medialpoints is injected
and lateral points is with 1.5with
injected U. 1.5
TheU.medial point
The medial (black
point (black dot)
dot) is
is interciliary point located on frontal notch that can be palpated. The lateral point (orange dot)isis
interciliary point located on frontal notch that can be palpated. The lateral point (orange dot) the
crossing point of mid-pupillary line and superciliary arch. Consent was
the crossing point of mid-pupillary line and superciliary arch. Consent was obtained by the volun- obtained by the volunteer.
teer. (ML; midline,(ML;
HL;midline, HL; horizontal intercanthal line, MP; mid-pupillary line, SA; superciliary arch).
horizontal intercanthal line, MP; mid-pupillary line, SA; superciliary arch).
4. Side Effects
4. Side Effects 4.1. Ptosis
4.1. Ptosis Treatment of glabellar frown lines with BoNT in 264 subjects included adverse effects,
such as transient headache (15%) and mild unilateral blepharoptosis (5.4%), resolved
Treatment of glabellar
mostly frown[15].
in one month lines
In awith BoNT in
meta-analysis by 264 subjects
Brin et included
al., adverse adverseeyelid
effects, including ef-
fects, such as transient headache
ptosis (1.8%) (15%)
and eyelid and mild
edema unilateral
were observed blepharoptosis
with (5.4%), resolved
BoNT, for the treatment of glabellar
wrinkles
mostly in one month [16].
[15]. In a meta-analysis by Brin et al., adverse effects, including eyelid
BoNT injected into the glabellar area can diffuse downward, paralyzing the levator
ptosis (1.8%) and eyelid edema were observed with BoNT, for the treatment of glabellar
palpebrae superioris muscle, which causes ptosis and is usually unilateral (Figure 6).
wrinkles [16].
BoNT injected into the glabellar area can diffuse downward, paralyzing the levator
palpebrae superioris muscle, which causes ptosis and is usually unilateral (Figure 6).
PEER REVIEW 6 of 9

Toxins 2022, 14, 268 5 of 8

Figure 6. A person with ptosis after botulinum neurotoxin injection into the corrugator supercilii
muscle. Consent was obtained from the volunteer.
Figure 6. A person with ptosis after botulinum neurotoxin injection into the corrugator supercilii
Almost
muscle. Consent was obtained from30–40% of the cornea is covered in the upper eyelid in patients with ptosis.
the volunteer.
Early literature described a 1–3% prevalence of ptosis, while an approved FDA clinical study
Almost 30–40% reported a prevalence of 5.4% [15,16]. This occurs when the lateral injection point is too
of the cornea is covered in the upper eyelid in patients with ptosis.
deep or when too much BoNT is injected. Therefore, lateral injections should be performed
Early literature described
superficially in the subdermalof
a 1–3% prevalence ptosis,
layer. Whenwhile
ptosisan approved
occurs, patientsFDA clinical
should be reassured
study reported a prevalence
that they ofwill5.4%
regain[15,16]. This occurs
their eye-opening whenThe
function. theeyelid
lateral injection
should pointand
be elevated is ptosis
too deep or when tooshouldmuchdisappear
BoNT iscompletely
injected. in mild cases.lateral
Therefore, Ptosis can occur forshould
injections up to 2–3
bemonths;
per- thus,
careful initial treatment is required.
formed superficially in the subdermal layer. When ptosis occurs, patients should be reas-
For symptomatic treatment, eye drops, including an α-adrenergic agonist that activates
sured that they will regain their eye-opening function. The eyelid should be elevated and
the Müller muscle, should be administered three times daily [13]. The Müller muscle,
ptosis should disappear completely
situated between the in levator
mild cases. Ptosis
palpebrae can occur
superioris for uphas
and mucosa, to 2–3 months;function
the auxiliary
thus, careful initial treatment is required.
of eyelid lifting. As the Müller muscle is innervated by sympathetic neurons, eye drops
For symptomatic containing
treatment, 0.5%eye
apraclonidine, an α-adrenergic
drops, including agonist, can agonist
an α-adrenergic contract the Müller
that acti-muscle
after it has been absorbed into the mucosa and can elevate the eyelid.
vates the Müller muscle, should be administered three times daily [13]. The Müller mus-
cle, situated between4.2.
theSamurai
levatorEyebrow
palpebrae superioris and mucosa, has the auxiliary func-
tion of eyelid lifting. AsSamurai
the Müller muscle
eyebrows is innervated
are adverse effects that by sympathetic
result neurons,
from the diffusion of BoNTeye
affecting
the medial part of the frontalis muscle (Figure 7).
drops containing 0.5% apraclonidine, an α-adrenergic agonist, can contract the Müller
Such diffused
muscle after it has been absorbed intoinjections of BoNT
the mucosa paralyze
and the medial
can elevate thepart of the frontalis muscle belly,
eyelid.
resulting in the lateral eyebrows moving upward and a subsequent angry appearance [12].
Lee et al. suggested that when samurai eyebrows occur, additional BoNT should be injected
4.2. Samurai Eyebrow along the superior temporal line, based on the established injection method. [17]
Samurai eyebrows are adverse effects that result from the diffusion of BoNT affecting
the medial part of the frontalis muscle (Figure 7).
Toxins 2022, 14, x FOR PEER REVIEW 7 of 9

Toxins 2022, 14, 268 6 of 8

Figure 7. A person with samurai eyebrows after botulinum neurotoxin injection into the corrugator
Figure 7. A person
supercilii muscle.with samurai
Consent eyebrows
was obtained after
from thebotulinum
volunteer. neurotoxin injection into the corrugator
supercilii muscle. Consent was obtained from the volunteer.
5. Discussion
SuchTo prevent
diffusedadverse effects,
injections of clinicians should pay
BoNT paralyze theattention
medial to various
part factors,
of the such muscle
frontalis as
theresulting
belly, injection point,
in thedose of BoNT,
lateral direction
eyebrows of the needle,
moving upward and position
and of the hand.
a subsequent The site
angry appear-
anceof[12].
injection is of
Lee et al.great importance
suggested for thesamurai
that when prevention of ptosis,occur,
eyebrows and it should be asBoNT
additional superior
should
as possible to the edge of the orbital rim. The location at which the CSM originates is right
be injected along the superior temporal line, based on the established injection method.
above the upper inner boundary of the orbital rim. One unit of BoNT is reported to spread
[17]over 1.5 to 3 cm; therefore, injecting a bit above the location where the CSM originates is
allowable [18,19].
5. Discussion
In a study by Yang et al., the origin and insertion points of CSM were anatomically
studied
To prevent[11]. adverse
The CSMeffects,
originates 16 mmshould
clinicians above thepayhorizontal
attention intercanthal plane and
to various factors, such as
4–14 mm from the midline, inserts into the dermis (30 mm above the
the injection point, dose of BoNT, direction of the needle, and position of the hand. The HL and 16–35 mm
sitefrom the midline) and interlinks with the frontalis muscle.
of injection is of great importance for the prevention of ptosis, and it should be as
In patients with chronic migraine, the CSM is targeted for BoNT injection because it is
superior as possible to the edge of the orbital rim. The location at which the CSM origi-
related to the entrapment of the supratrochlear nerve within the CSM. Clinically, 5 U of
nates
BoNT is right above
injection the upper
per CSM has beeninner boundary according
recommended, of the orbital
to therim. One unit
PREEMPT trial of BoNT
[20]. In is
reported
the study,to spread
Lee et. over 1.5 to 3 that
al. proposed cm; injecting
therefore, injecting
a lower dosea of
bit5 above the location
U at a defined where the
anatomical
CSM originates is allowable [18,19].
site produces the same therapeutic effect with a safer side effect profile [21].
In aInstudy by Yang
the clinical field, et al., injections
many the originareand insertion
performed points
on the of CSM
eyebrows, wereare
as they anatomically
usually
located
studied along
[11]. ThetheCSMupper inner boundary
originates 16 mmofabove
the orbital rim [14]. However,
the horizontal in elderly
intercanthal patients,
plane and 4–14
if the location of injection is selected based on the eyebrows,
mm from the midline, inserts into the dermis (30 mm above the HL and 16–35 mm from there is a high probability
the of ptosis, as their eyebrows are lowered during the aging process [13]. In patients with
midline) and interlinks with the frontalis muscle.
lowered eyebrows, one can mistakenly inject below the boundary of the orbital rim. The
In patients with chronic migraine, the CSM is targeted for BoNT injection because it
injection was performed slowly to avoid the BoNT from dispersing down to the eyelids [13].
is related
Duringtothe theinjection,
entrapment manual of the supratrochlear
blocking was performed nervealong
withinthethe CSM.
inner Clinically,
boundary of the5 U of
BoNT injection
orbital per CSM has been recommended, according to the PREEMPT trial [20]. In
rim [13].
the study, Lee et. al. proposed that injecting a lower dose of 5 U at a defined anatomical
site produces the same therapeutic effect with a safer side effect profile [21].
In the clinical field, many injections are performed on the eyebrows, as they are usu-
ally located along the upper inner boundary of the orbital rim [14]. However, in elderly
Toxins 2022, 14, 268 7 of 8

Broad and precise anatomical knowledge of the muscles is essential for attaining the
maximum effect with the lowest possible amount of BoNT. We reviewed the strategies used
in previous studies, and the injective strategy varied in each study. As wrinkle correction
via BoNT is frequently conducted, side effects, such as paralysis of adjacent muscles and
ptosis, have been reported.
The limitation of this study is that the review was based on anatomical information
and was not a clinical study. Further, clinical study should be conducted. However, the
study is significant in the usage of a minimal amount of BoNT and the location is based on
anatomical information that can be easily applied.

6. Conclusions
In summary, 6 U of CSM BoNT should be injected, with 1.5 U injected into each medial
and lateral point.
The medial point is the interciliary point located on the frontal notch that can be
palpated. The lateral point is the crossing point of the mid-pupillary line and superciliary
arch (Figure 5).
This study performed an extensive analysis of published research on the anatomy of
the CSM to provide an anatomical proposal for glabellar frown line correction.

Author Contributions: Conceptualization, K.-H.Y.; writing—Original Draft Preparation, K.-H.Y.;

writing—Review and Editing, J.-H.L. and H.-J.K.; visualization, H.-W.H.; and supervision, H.-W.H.
and H.-J.K. All authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by the Korea Medical Device Development Fund grant, funded
by the Korean government (the Ministry of Science and ICT, the Ministry of Trade, Industry and
Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (Project Number:
1711138194, KMDF_PR_20200901_0109-01).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Consent was obtained by the volunteers.
Data Availability Statement: Not applicable.
Acknowledgments: The authors sincerely thank those who participated so that anatomical research
could be performed. Results from such research can potentially increase mankind’s overall knowl-
edge, which can then improve patient care. Therefore, these participants and their families deserve
our highest gratitude. The authors thank Eun-Byul Yi from Eonbuk elementary school for illustrations.
Conflicts of Interest: The authors declare no conflict of interest.

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